In a career that has generated 54 singles titles, including 16 grand slams, Williams has won just about everything there is to win in her sport but Cincinnati, one of the WTA Tour's most prestigious tournaments, is not on that very long list.
If the world number one is to add a 55th title to her haul here she will have to perform at a much higher level than she did against the plucky but overmatched 19-year-old Canadian.
"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, who was playing in her first match since Sunday's crushing win over Sorana Cirstea in the Toronto final. "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.
"So it was just some crazy tennis out there."
Staring across the net at a number one ranked opponent for the first time, Bouchard registered an early shock when she broke Williams to open the match and held serve to go up 2-0.
Williams, who has already matched a career high this season winning eight titles, won the next two games but Bouchard would not back down breaking her opponent a second time on way to taking the first set.
In the second set, the powerful Williams would begin to show her class registering the early break to take the set and level the match then doing just enough in the third to finish off the 62nd ranked Bouchard.
Despite piling up 49 unforced errors, more than double the 23 from Bouchard, Williams still had enough weapons, including seven aces, to get the job done and run her match record this season to a stellar 57-3.
Italian sixth seed Sara Errani and her 12th seeded compatriot Roberta Vinci both advanced to the third round with testing three set wins.
Errani outlasted Slovenian qualifier Polona Hercog 6-4, 5-7, 6-4 while Vinci was a 6-4, 6-7 (3), 6-3 winner over Germany's Andrea Petkovic.
Australian 11th seed Samantha Stosur, the 2011 U.S. Open winner, had smoother passage taming American Jamie Hampton 6-3, 7-6 (3).
Results from the ATP and WTA Western and Southern Open (x denotes seed):
Andy Murray (GBR x2) bt Mikhail Youzhny (RUS) 6-2, 6-3
Tommy Haas (GER x11) bt Marcel Granollers (ESP) 6-4, 6-1
David Goffin (BEL) bt Vasek Pospisil (CAN) 7-5, 1-6, 7-6 (8/6)
Juan Martin Del Potro (ARG x7) bt Nikolay Davydenko (RUS) 7-5, 7-5
Feliciano Lopez (ESP) bt Jrmy Chardy (FRA) 6-4, 2-2 ret
John Isner (USA) bt Richard Gasquet (FRA x8) 7-6 (8/6), 6-2
Samantha Stosur (AUS x11) bt Jamie Hampton (USA) 6-3, 7-6 (7/3)
Sara Errani (ITA x6) bt Polona Hercog (SLO) 6-4, 5-7, 6-4
Roberta Vinci (ITA x12) bt Andrea Petkovic (GER) 6-4, 6-7 (3/7), 6-3
Serena Williams (USA x1) bt Eugenie Bouchard (CAN) 4-6, 6-2, 6-2