Orbetello sits on the Tirrenica railway line between Rome and Pisa. The local station, Orbetello-Monte Argentario, is on the mainland about 4 km from the old town with regular bus and taxi connections across the causeway. Most regional trains from Rome Termini (about 1h45) stop here; the slower ones from Grosseto (35 minutes) too.
By car, the SS1 Aurelia runs along the coast and is the fastest route from both Rome (around 2 hours) and Florence (about 2h30). Parking inside the walls of the old town is restricted — leave the car at one of the lots on the causeway and walk in.