Williams rallied to defeat 60th-ranked Chanelle Scheepers 4-6, 6-2, 6-3. After Kevin Anderson beat Isner 7-6 (0), 7-6 (5), the match came down to mixed doubles. Williams and Isner beat the South Africans 6-3, 6-2 to clinch victory.
Williams took some time to settle in against an opponent who rallied well and hit the ball deep. Scheepers broke Williams at love to serve for the first set. But after that, the seven-time Grand Slam champion looked increasingly comfortable and began to play more aggressively.
Williams clinched the second set when Scheepers double-faulted. She then won the first four games of the third.
Williams was playing for the first time since winning at Luxembourg in mid-October.
"I was just trying to find some rhythm out there," she said. "She's obviously a really good player having maintained a top-40, top-50 ranking the last couple of years. She played a match yesterday, too, so had an extra advantage. It felt good out there.
"I'm not expecting to be perfect now, but I'm thinking that my game will get better every match. I think the doubles will help as well to hone everything. More than anything I was just so excited to be out there playing, and I'm ready to go for it."
Tsonga beat Verdasco 7-5, 6-3 in the singles, and Medina Garrigues defeated Johansson 6-3, 6-2.
Andrea Petkovic, who retired with a right knee injury against Australia on Saturday, has withdrawn from the competition with a ruptured meniscus and will miss the Australian Open. She will be replaced by Tatjana Malek for Germany's remaining matches against Italy and Serbia.