Depends on what you wanna see or do.
Plzen and Ceske Budejovice have the mother ship brewery tours. Plzen was liberated by the US so there are historical markers and monuments. Also, a huge synagoauge from 1893.
Karlovy Vary is great for meandering along the colonnade on a nice Autmun day. As well, a thermal pool experience if interested. KV by bus is the most practical method.
Karlstejn castle is about 40 mins out.. an easy 1/2 day visit Trains every 30mins. Or Krivoklat castle nearby which is in a more natural state and little or no tourists.
Cesky Krumlov warrants an overnight stay if possible.
The only feasable across the border visit would be Dresden Germany..just over 2 hours
If you can indicate your dates, we can locate events or festivals that might occur during your stay. You will be at the tail end of wine/ harvest festivals
There are a couple of farmers markets on SAT. in Prague Smaller marekts during weekdays.
I am an Expat living near Prague for many years.... If you need ideas or suggestions, just ask or you can send a PM
Happy planning!!