The town is located in the Simitli Valley at the foothills of the Rila, Pirin, and Vlahina mountain ranges.

Geographical locations of note are the Komatinski Cliffs between Brestovo and Sushitsa, the Kresna Gorge along the Struma, and the foothills of the Pirin Mountains at Senokos.

Simitli lies along the parallel Struma motorway and first class I-1 road along the Struma valley, part of European route E79, that link the capital Sofia and the provincial centre Blagoevgrad with Greece at Kulata.

At Simitli the second class II-19 road branches off I-1 heading to the town and winter resort of Bansko in the Razlog Valley.

Simitli is also part of the Bulgarian State Railways network from Sofia to Greece.