Spain itinerary with the concept similar to Italy's Tuscany

Of course you can do it. It’s really a matter of how far away from Madrid you want your bases to be, which direction from Madrid you want to travel, what you decide you want to do, large or small town, and time of year. Possible bases could include Salamanca, Zamora, León, Burgos, Cáceres, Zaragoza or any other number of towns.

I just did this, modeling my trip on my several successful driving trips in Italy. A couple differences you may find: drives can be looong (roads in great condition. but not highways with high speed limits); gas stations not immediately off the highway but a short drive away; no ZTL, but sometimes similar driving restrictions in old towns--parking is often best in a parking garage.
We could not settle on either Castile-La Mancha or Extremadura, so we did both. We stayed two nights in Cuenca, which we loved, then we drove over to Caceres for five nights.
We are still a little hesitant about indoor activities since we have not had covid yet (and had to test to return), so we did a lot of hiking, which was extraordinary. We also ate outdoors just about every meal, and the fabulous weather supported that well. I think April would be as nice as late May, since we did have a minor heat wave.

I think that the region of Extremadura, just west of Madrid, will fit the bill. Should be lovely in April too, with rolling green hills, fields of wildflowers, and groves of oak trees.

Extremadura is often overlooked and really underappreciated, in my opinion, it's one of Spain’s most fascinating regions. It's full of time-warped old towns, castles, monasteries, and beautiful countryside, and was the homeland of many Conquistadors. And also the best Jamon Iberico in all of Spain comes from this region!

You can fly in to Madrid, pick up a car, then head west into Extremadura. I'd recommend these places

Cáceres (home base): The old town of Cáceres is a UNESCO World Heritage Site and has a mix of Roman, Islamic, Gothic, and Renaissance styles.

Parque Nacional de Monfragüe: Day trip from Cáceres to this biosphere reserve, includes stunning cliffs & rock formation, plus many kinds of wildlife (especially noted for its Griffon vultures). Has some really great hiking trials.

Trujillo: This town is where some of Spain’s most famous(infamous) conquistadors came from. The town has a few baroque and Renaissance palaces and an interesting Museum of Francisco Pizarro, who led the expedition that conquered the Inca Empire.

Guadalupe: Has the beautiful Real Monasterio de Guadalupe. You can tour this monastery and its collection of art, jewels, illuminated manuscripts. You can also see two cloisters, one late-14th-century Mudéjar, the other Gothic.

Mérida (home base): Mérida is the provincial capital and has some of the best Roman ruins in Spain.

Zafra: On the way to Zafra stop by Castillo de Feria, an originally Moorish hilltop fort. Zafra itself is a white walled town nicknamed "Little Sevilla" and feels very "Moorish".

Jerez de los Caballeros: A very picturesque small town. The old town is surrounded by a Moorish wall with six gates. After it was conquered from the Moors, the town was transferred to the Knights Templar, who left their own architectural mark.

Monesterio: an unassuming little town that produces some best Jamón ibérico in all of Spain. You can find the real Museo del Jamón there, not those touristy ones you will find in Madrid.

At the end you can drive down to Sevilla, drop off your car, spend a few days in the city, before taking the AVE high speed train back to Madrid to fly out.

I'll add to Carlos's excellent list for Extremadura--one of my favorite day trip was to the Roman bridge at Alcantara and hiking in Tajo National Park. I'd return to any of the places we visited, but this landscape really captivated me.
Near Caceres, we visited a small park called Los Barruecos with interesting rock formations and lots of wildlife.

Southern Spain in April is heaven, green mountains, wild flowers, baby farm animals. If your super lucky you will be there the first week of April as Easter is the 9th in 2023 and the week before will be Holy Week and that is amazing. There are lots of nice hiking trails in southern Spain, look into Caminito del Rey more of a walk than a hike but you wont find this special type of thing hardly anywhere else. J

Carlos - thank you so much.
Question - is spending all 12 days in Extremadura is ok and the best utilization of the time? If I have 3 days allocated to Madrid and Seville each, should we spend the rest 6 days between Caceres and Merida each (including all day trips you've mentioned); OR should we add another home base somewhere else?

@ Nemo
Hi, I think you should just focus on these home bases Madrid (2-3 days), Cáceres‎ (3 days), Merida (3 days), Sevilla (3-4 days). That would make for a fine roadtrip :)

I like Carlos's idea. For future reference, should you decide to do this again, but in the summer, I think it would be a fun way to explore the Basque Country or Galicia.

Not Carlos, but I hope my recent trip experience is helpful. It would depend on your wish list and how much you like to drive vs changing bases. We stayed in Caceres and visited Merida from there; it was about an hour drive. I preferred Caceres but staying in Merida would have allowed us more time to fully explore the museum (we're not early risers). It would also be a good base for visiting some of the towns on the southern end, which we did not get to on this trip. If you end up with more places you want to see in the center and north of Extremadura, then you could probably just stop in Merida en route to Sevilla.

PS: I was thinking, when you will be based in Merida, since you will have a car, you could even make a daytrip into Portugal. It's a little over 1:30 hr to Évora in Portugal, which I think Rick Steves recommends highly - https://www.ricksteves.com/watch-read-listen/read/articles/peeling-back-evoras-layers-of-history

I'm pleased to see Extremadura get the positive attention it deserves. I haven't been to all the places Carlos mentioned, but I'll personally "second" those I've visited. A couple of brief notes:
If you're a chess player, note that Zafra, though not his birthplace, was home to Ruy Lopez de Segura for several of his adult years.
Also, when in Merida, and depending on your interests, you may want to check out John Lennon street.

Thank you so much everyone. Will take everyone's advice and build upon it.
Question for everyone who was recommending Extremadura before I dive into booking. If Im taking basis as Cáceres and Merida - are they lively enough in the evening for a 25 yo. My son will join us for this trip and I know he really enjoys good evening meal and an evening stroll along the somewhat busy main town/city street. I know I will thoroughly enjoy the area - want to understand if Cáceres and Merida will work from that perspective. With Italian analogy - are they like Montepulciano or more like Siena?

Cáceres and Mérida will probably be the most lively places in Extremadura. Mérida is the regional capital.

It's been a while since I've been in Caceres (2006) and Merida (2014), but I do recall they had their distinct night-life areas. I'm not a night-life person myself, but I do remember a long street in central Merida -- possibly Sagasta, but I'm not certain -- that seemed quite lively at night. Of course I'm recalling only a couple of nights from over seven years ago.

If you rent a car in Madrid and expect to go south to Seville and or Cordoba, you will be driving a lot more. You can see places Cordoba and Seville by taking the train.

From Madrid, you can do day trips to Segovia and Toledo by rail.
Visiting more distant places like Salamanca or the area near the Portuguese border, you might want to rent a car.

Circling back to the advice to visit Evora. Should I cut 1 night from Merida and stay 1 night in Evora or Evora is just a day trip?

cut 1 night from Merida and stay 1 night in Evora

That could be interesting, I'd say go for it!

Both work, really. I don't like changing hotels for A night, so I'd be inclined to do a day trip. The drive from Merida to Evora is very easy on the interstate-like highway, so you could come back at night.

Merida felt very lively--we were there during the day, but it had a definite buzz. I don't think anyone of any age would have trouble finding something to do.
In Caceres we of course focused on the picturesque old town, where there were primarily Spanish tourists enjoying the squares. Your son may want to explore the newer part of town that cascades down from old town as well. We were over there a lot during the day and it was vibrant. Surprisingly May felt somewhat sedate as I imagine summer is so so hot.

We have done two trips like this in Spain in the last four years, both times into Barcelona and exploring Costa Brava. We rent a home and venture out from there as not a fan of moving and unpacking, there is always plenty to do and we always feel like we just scratched the surface when we depart. Not everyone's cup of tea but how we like to travel. We just returned from two weeks in Begur (under 90 minutes from Barcelona) and you can hit great quaint towns, in addition to Begur, in under 30 minutes (Pals, Peratallada, Llafranc) and go further afield to Girona (1 hour) or Cadaques (90 minutes) and Coillure in France (>2 hours) for museums, history etc. The hiking is spectacular along the Cami de Ronda (coastal hikes) and the many beaches/coves are fabulous as well (but the Med in April will be too chilly). Enjoy the planning and research...Spain is a fabulous country and we look forward to seeing more of it!