The town is named after Louw Wepener, the leader of the Boers in their war with the Basotho chief Moshoeshoe I in 1865.

Wepener was the southernmost of several settlements founded by the Free Staters in the "conquered territories" to prevent the Basotho from resettling the land taken from them during the war of 1865.

During the Anglo-Boer War, a British and South African colonial garrison of 2,000 men under Colonel E. H. Dalgety was besieged by the Boer commandos under the command of General Christiaan de Wet at Jammers drift on the Caledon River.

The siege lasted 17 days, until reinforcements arrived on 25 April 1900 to end the battle in favour of the British.

Other facilities in the village include various general stores, builders merchant, sports club, furniture stores, butchery, 2 banks, doctors surgeries, post office, fuel stations, police station and Magistrate's Court.