[11] In 2017, after a 30.81 seconds victory in the seldom-run 300 metres distance, breaking Michael Johnson's world-best time of 30.85 which was set in 2000, Van Niekerk became the only sprinter in history to have run sub-10, sub-20, sub-31 and sub-44 performances at 100m, 200m, 300m and 400m respectively.

[19] He made his international debut at the 2010 World Junior Championships in Athletics, where he placed fourth in the 200m with a personal best time of 21.02 seconds.

[20] His senior breakthrough came at the age of eighteen at the 2011 South African Athletics Championships when he won the 200m title in a new personal best time of 20.57 seconds.

He won the second national title of his career over that distance at the 2013 South African Championships, winning with a sub-46-second time.

[25] He managed to reach the podium and receive his first international medal in the 4×400 metres relay as the South African men took the silver.

[20] A national title win in April 2014 saw Van Niekerk top the world rankings with a best of 44.92 seconds—his first sub-45-second run.

After a win at the FBK Games in the Netherlands, he ran at the New York Diamond League race and placed second to LaShawn Merritt.

[22] He entered both sprint events at the 2014 Commonwealth Games and won his first individual senior medal over 400m, placing behind Kirani James with a time of 44.68 seconds—his second-fastest run at that point.

On July 4, 2015, Van Niekerk lowered his South African record to below 44 seconds with a 43.96 at the Meeting Areva and ranked himself in the all-time top 12 whilst beating Kirani James for the first time.

A month later, Van Niekerk represented South Africa at the 2015 World Championships in Athletics, focusing solely on the 400m.

Winning his heat, Van Niekerk beat LaShawn Merritt, with the defending champion taking second.

The results repeated in the final, as he won gold in 43.48 seconds, making him the fourth-fastest runner of all time, ahead of Merritt who was running his personal best as the sixth-fastest in 43.65.

On 31 October 2017, Van Niekerk participated in a celebrity-funded rugby match sponsored by FC soccer.

[36] On 31 May 2019, it was announced that he would run at the IAAF Diamond League event in London in July, his first major race since his comeback from injury.