The ancient Roman road Via Militaris connecting Balkans, central and Western Europe had a similar route to the modern-day A4 motorway.

[citation needed] The first section of the motorway were 3 km from Trupale interchange to Komren on entrance in Niš which was constructed in the period 1990–1992.

Construction of the Komren — Prosek section, which is usually referred as Niš bypass, started in 1998, but was cancelled due to the war in Kosovo and NATO intervention.

In August 2017, the first carriageway of motorway was opened of 5.1 kilometers-long part of section Staničenje — Pirot east from end of bridge Nišava 4 to Sarlah tunnel.

[citation needed] In March 2018, full-profile motorway was completed on 5.1 km-long part of section Staničenje — Pirot east on which the first carriageway was opened in 2017.