If you travel from Zagreb and Split you drive on the highway all the way to Ploce. There is a ferry in Ploce driving to Trpanj and once you get to Trpanj you have 20 minutes drive to Orebic. In case you do not prefer ferry, after you get off the highway, you have to drive to Adriatic motorway to east through Neum until you reach crossing to Peljesac. Once you get on Peljesac road you have approximately one hour left till you reach Orebic.
Dubrovnik, Zagreb and Sarajevo have bus routes connections with Orebic.
Coastal line connects Rijeka, Split and Dubrovnik, it stays even in Korcula during summer months. From Korcula to Orebic you can arrive either with ferry of small passenger ship within 15 minutes. There is also catamaran line driving from Split to Korcula and this is the fastest relation which connects these towns on daily basis, while local ship company connects Orebic and Korcula according to catamaran schedule.
In case you arrive from larger European towns, there is an airport in Dubrovnik as a best choice since from Dubrovnik you get quite quick to Orebic. From this airport there is a possibility of transfer to Dubrovnik bus station and you can take a bus to Orebic. There is also rent-a-car or taxi service available.