Seven-times major winner Williams, diagnosed in 2011 with an auto-immune, fatigue inducing illness, played just 18 matches this year as she battled a lower back injury but a return to Arthur Ashe Stadium seemed just the tonic.
The 33-year-old American celebrated opening day on centre court at the season's final Grand Slam by extending her first-round record at the US Open to 15-0 in avenging a first round defeat to Flipkens two weeks ago in Toronto.
"I expected a much better Venus today. She was on fire," said Flipkens, a semi-finalist this summer at Wimbledon. "It was her first match in Toronto since the French Open.
"Here, it's like her play garden. It's on Arthur Ashe in her home country. I think it's the worst draw you could have as a top 32 seed."
Williams, who won US Open titles in 2000 and 2001, raced through the opening set in 27 minutes and then withstood some long rallies to clinch victory with a service break in the last game to clinch her place in the second round.
"For me, I stay positive because I know I can play great tennis," said Williams, who was 11-7 in matches leading up to the US Open. "Sometimes you just have to go through more than what you want to go through.
"When I had losses, it always motivates me a lot to do better and to work harder.
"I haven't had a lot of chance to play this year or a lot of chances to play healthy this year. So I'm just going to have to keep working my way into it ... but I know I can do that."
Flipkens said Venus was still capable of great things.
"When Venus is on fire, she is on fire. I didn't get many chances," said the Belgian, who was 1-for-6 on her breakpoint opportunities.
"If Venus is fit and she's focused she's a top 10 player. Today she was like a top 10 player."
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