Top seed Williams, a five-time champion, was playing for the first time since her embarrassing French Open second round exit against Garbine Muguruza and the world number one needed only 61 minutes on Centre Court to ease past fellow American Anna Tatishvili 6-1 6-2.
Blitzing the Georgian-born world number 113 with 31 winners and 16 aces, Serena, a 17-time Grand Slam champion, raced through to a meeting with South Africa's Chanelle Scheepers.
Serena admitted she had struggled a little with the slick grasscourt, occasionally losing her footing and suffering a few bumps and bruises.
"I think I'll be OK. I'll see tomorrow. It was weird. I was fell so many times," she said.
Romanian third seed Simona Halep saw off Brazil's Teliana Pereira 6-2 6-2.
Retired women's champion Marion Bartoli returned to Centre Court only to hear herself introduced as 'Maria' by a blundering announcer.
The Frenchwoman performed the coin toss ahead of the first round match between Sabine Lisicki, the German she defeated in the final last year, and Israel's Julia Glushko.
Lisicki was untroubled, winning 6-2 6-1 in just 57 minutes.
Polish fourth seed Agnieszka Radwanska, the 2012 runner-up, beat Romania's Andreea Mitu 6-2 6-1 but seventh-seeded Jelena Jankovic was knocked out, losing 6-3 6-2 to two-time quarter-finalist Kaia Kanepi of Estonia.
Michelle Larcher de Brito, who shocked Sharapova last year, defeated two-time major winner Svetlana Kuznetsova, the Russian 28th seed, 3-6 6-3 6-1 while Italian 14th seed Sara Errani lost to France's Caroline Garcia 2-6 7-6 (7/3) 7-5.
-AAP