Middelburg was established as Nasareth, (root from dry land), in 1864 by the Voortrekkers on the banks of the Klein Olifants River. The name was changed in 1872 to Middelburg to mark its situation midway between the Transvaal capital Pretoria and the gold mining town of Lydenburg. A Dutch Reformed Church was built in 1890 and became a focal point in the area. The British built a large concentration camp in Middelburg during the Second Boer War. The Memorial Museum was built at the site next to the 1,381 graves of women and children died here.Across the ridge on the north-western side towards Botshabelo, the township of Mhluzi developed simultaneously and became part of greater Middelburg in 1994.

The town also has its share of places of historical interest, including the White Church which was built in 1890. The church was used by British soldiers during the second Anglo Boer War and is one of the few remaining structures that wasn't destroyed during the war. The Meyer's Bridge, built in 1896, has remained standing for over a century, surviving numerous floods. This national monument was created as a road link between Lydenburg and Middelburg at the turn of the century. Middelburg, the birthplace of celebrated playwright Athol Fugard, is in the heart of "Jock of the Bushveld" country.