Plzeň is 90 km southwest of Prague and very easy to reach by train. Direct fast trains from Prague's main station (Praha hlavní nádraží) run roughly every hour and take about 1 hour 20 minutes; slower regional trains take 1 hour 40 minutes. The Plzeň main station (Plzeň hlavní nádraží) is a 15-minute walk east of the old town, or a quick tram ride.
By bus, RegioJet and FlixBus run services from Prague's Florenc bus station in about 80 minutes — marginally faster than the slow train but less comfortable. Driving from Prague on the D5 motorway takes about an hour with no traffic; note that Plzeň sits on the same road that continues to Nuremberg, making it a natural stop on a Prague–Bavaria road trip.
There is no major airport in Plzeň. The nearest international airport is Prague Václav Havel (PRG), from which you connect by train or bus as above.