Van Niekerk, who stopped the clock in 43.62 seconds, did not have everything his own way initially and found himself in second place behind Baboloki Thebe of Botswana entering the home straight.
The Olympic champion never panicked however, easily catching Baboloki and powering away to win in emphatic fashion without really having to push himself.
Baboloki finished second in a time of 44.02 followed by Isaac Makwala, also of Botswana, in 44.08.
Earlier Akani Simbine finished third in the 100m in a time of 9.99 seconds in a race won by Justin Gatlin of the United States. Heinrico Bruintjies finished in sixth place.
In the 400m hurdles, both LJ van Zyl and Cornel Fredericks finished outside the podium places in seventh and fifth respectively while Sunette Viljoen could only finish in sixth in the women's javelin competition with a throw of 61.38m.
Watch Wayde Van Niekerk in the 400m - Lausanne Diamond League 2017
Playlist of races from Lausanne Diamond League 2017