Spain and Portugal or Italy and Greece in October?

Does it have to be a two-country trip? Two weeks is short; I wouldn't want to split the time between either of those pairs of countries. You'd need to fly between Italy and Greece, and probably again within Greece to get to an island. As for the Spain-and-Portugal combination, the map suggests that would be a fine idea, but in the real world it's challenging. There's very little cross-border transportation.

I'd pick one of those four countries.

This is like asking for preferences between Rioja and Montepulciano wines. What do you like doing? Art, Beach, etc. Pick one country, change locations twice or at most three times... Relax! See Rick Steve's Travel Skills Videos and videos on each of your potential locations.

I could see pairing parts of Spain and Portugal with them being adjacent, but there is no way I could tear myself away from Italy or Greece after only a week. Any of the four would be great for two weeks!
You can find lots of sample itineraries online or in guide books. Maybe it might help to work backward, like determine where you would fly (for example, for Athens, first decide how much time you'd like to spend in Athens, then decide if you want to visit islands or the mainland, how you want to travel, etc.).

I have been to Portugal more times than anywhere else, so this would get my vote. It’s an ideal length of time to explore the area between Lisbon and Porto. Also see Evora, Coimbra, Alcobaca and Batalha - all pretty towns and some lovely scenery.

With only 2 weeks, stick to one country wherever you decide to minimise travelling and making it easier to get a return ticket rather open jaw.

I have had good and some bad weather in October in all your options (except I haven’t spent time in Italy in October).

We have had wonderful weather in Italy during October. Magnificent fantastic country, not much compares. We have spent 2 years there and still have much to see.

One country for two weeks. Be there instead of seeing there.
A wonderful opportunity to peel away several layers of experiencing a journey.

We did 2+ weeks in Portugal end of August / early September in 2019 ... started in Lisbon, over to the coast, up to Porto, all the way back down the middle of the country to the Algarve and back to Lisbon ... great country, awesome weather, fabulous food (especially if you like seafood), nice people, everything about it was great ... I'd go back in a minute.

Thank you all so much for your insights! We think we are going to choose going to Greece since we have never been there and it has been on my bucket list for years :)