Thusi is the host of Lip Sync Battle Africa on MTV and e.tv, as well as the talk show Moments, on EbonyLife TV. She has starred on the SABC 3 popular soap opera, Isidingo, as Palesa Motaung, co-hosted Live Amp with DJ Warras and Luthando Shosha, the SABC 1 celebrity gossip magazine show, Real Goboza.

In 2009, Thusi starred as Patricia Kopong on the BBC/HBO comedy-drama, The No. 1 Ladies’ Detective Agency.

In 2015, Thusi co-starred in Tremors 5: Bloodlines. She also appeared in a music video entitled “Pearl Thusi” by Emtee.

In 2016, Thusi was cast in a series regular role as Dayana Mampasi on the second season of the ABC thriller series Quantico. In the same year, Thusi was cast as Samkelo in the romantic drama film Catching Feelings. The film was released in theaters on March 9, 2018.

In 2017, Thusi starred as Brenda Riviera in the drama film, Kalushi.

In 2018, Thusi became the new host of the third season of MTV Base‘s Behind the Story. In the same year, Thusi was cast in the lead role of Queen Sono on the Netflix crime drama series Queen Sono. The series premiered on 28 February 2020.