The American was broken in the very first game and then again in the fifth on her way to losing the opening set to an opponent ranked 64 in the world.
However Williams began to move through the gears in the second set and, despite piling up 49 unforced errors, eventually saw off Bouchard after just short of two hours on court.
The 16-time grand slam winner admitted afterwards that she would need to improve if she was to win the tournament in Cincinnati for the first time in her career, branding some of her shots "embarrassing".
"Every ball I hit seemed to be going out and I even had the easiest approach shot and it went not slightly wide, it was like 50 feet out," said Williams. "That was actually embarrassing.
"I thought I'd never hit a shot like that professionally. I have maybe in practice with my eyes closed but never conscious have I hit a shot like that."
While Serena came through in three sister Venus tumbled out after going the distance against Russian Elena Vesnina, losing 6-2 5-7 6-2.
Italian sixth seed Sara Errani had to work hard to go through, eventually seeing off the challenge of Slovenian Polona Hercog 6-4 5-7 6-4, while seventh seed Petra Kvitova defeated Marina Erakovic of New Zealand 6-4 6-7(9/7) 6-3.
Australian Samantha Stosur, seeded 11th, was a 6-3 7-6 (7/3) winner over Jamie Hampton and Roberta Vinci of Italy came out on top 6-4 6-7 (3/7) 6-3 against German Andrea Petkovic.
There were also victories for seeds Caroline Wozniacki and Jelena Jankovic, who knocked out Monica Niculescu and Ekaterina Makarova respectively.