Lyon became just the sixth Australian to reach the prestigious milestone when he had Kagiso Rabada stumped by Tim Paine.
The 30-year-old finished with match figures of 5/145 to go with an impressive knock of 47 off 38 balls in the first innings of Australia's 322-run loss to the Proteas.
Sixers quick Mitchell Starc claimed a wicket in each innings of the match, which made headlines for the ball-tampering controversy involving the Australian team.
Meanwhile, Sixers WBBL stars Ash Gardner, Alyssa Healy and Ellyse Perry have been in action for the Southern Stars in the Women's T20 Tri Series.
Gardner (2/22) and Perry (2/31) were amongst the wickets in Australia's six-wicket win over India in the opening match on Thursday.
In the Southern Stars next match against England on Friday, Healy (31 off 23 balls) and Gardner (28 off 16 balls) both made handy contributions at the top of the order as Australia posted a competitive total of 8/149.
However, England made light work of the run-chase, securing an eight-wicket win.
Australia are back in action against India at 3:30pm today. You can watch the match live on Fox Sports or follow it at cricket.com.au.