Wales will play world champions South Africa and New Zealand, a stern test of their early progress under new coach Wayne Pivac.
The Welsh Rugby Union announced the traditional November fixtures on Wednesday, which also includes games against Fiji and Argentina at the Principality Stadium.
Fiji will open the series on November 7, before Pivac is pitted against fellow countrymen New Zealand the following week.
Argentina are the third opponents on Sunday, November 22, before the Springboks contest the final game on November 28.
"We will be testing ourselves against four of the best sides in the world this autumn and face the current top two in New Zealand and South Africa," WRU chief executive Martyn Phillips said in a media release.
"To maintain aspirations of winning the World Cup in 2023 we need to continually face the top teams, match them and regularly beat them.
"The stage is set for one of the toughest Autumn Series campaigns ever seen in Cardiff, but I know the whole of Wales will relish the challenge."
Wales are currently involved in the Six Nations, while they will also head out for a two-match tour to New Zealand and a one-off game against Japan in July.