Three-times champion Williams, playing her first match since falling to Simona Halep in the Wimbledon final, married her trademark power with quick movement and a steady stream of booming serves to overwhelm Belgian Mertens.
"It feels good," Williams said of her return to the hard-court surface. "Definitely feels different as I didn't play a ton this year on hardcourts but it feels good to be back out here."
Williams is keen to get more hard-court matches in before going for a record-equalling 24th career Grand Slam title at the Aug. 26-Sept. 8 U.S. Open and she took some time to hit her stride on Wednesday.
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After a pedestrian start, Williams raised the intensity during a lengthy four-deuce service game in the first set that she closed out with a thundering ace to go ahead 4-3 and set the tone for the rest of the 75-minute match.
She went on to win six of the final seven games to seal the win.
Williams will face Russian qualifier Ekaterina Alexandrova in the last 16 and a win would set up a potential quarter-final with U.S. Open champion Naomi Osaka, which would be their first encounter since last year's controversial New York final.
Earlier on Tuesday, Japanese second seed Osaka won the first set against Tatjana Maria 6-2 and advanced when the German qualifier retired.
"I thought I played really well despite the fact that we only played one set," said Osaka. "I'm just happy that it was my first match in a while and I was able to get in the groove of things quickly."
By reaching the last 16, Osaka is set to unseat Australian Ash Barty, who lost her second-round match on Tuesday, as world number one next week, though Karolina Pliskova also has a chance to reclaim top spot if she reaches the semi-finals.
The Czech third seed beat American qualifier Alison Riske 6-4 6-7(4) 6-2 and will next face Estonian Anett Kontaveit, who was beating Carla Suarez Navarro 7-5 3-1 when the Spaniard retired with a hip injury.
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