Known as the Economic Partnership Agreement (EPA), the deal was signed off by EU Commissioner for Trade Cecilia Malmström and trade ministers from Botswana, Lesotho, Mozambique, Namibia, Swaziland and South Africa.
The EPA does gives the African nations access to the EU's single market of 500 million consumers.
"Under the EPA, it will also become easier for companies and consumers to source European products that are needed here," Malmstrom said.
The EPA takes account of the different levels of development of each partner. It guarantees Botswana, Lesotho, Mozambique, Namibia and Swaziland duty-free, quota-free access to the European market.
In 2015, the EU imported goods worth almost 32 billion euro from the region, mostly minerals and metals. The EU exported goods of the nearly same value, mostly engineering, automotive and chemical products.