The eighth-seeded Williams, an eight-times grand slam winner, needed 77 minutes to dispatch the 19-year-old Kerber.
"I didn't play well at all, at all," said 25-year-old Williams, who has been bothered by a sore left thumb and was playing in her first match since losing in the Wimbledon quarter-finals to Justine Henin.
Williams, often left short of breath after being sent corner to corner by the German lefthander, served for the match at 5-4 in the second set but Kerber rose to the occasion, scoring a service break set up by a crosscourt passing shot.
That seemed to motivate the American, who broke right back and then served out the match as 67th-ranked Kerber netted a forehand on double matchpoint.
Williams was at a loss to explain her lacklustre performance, joking that perhaps she was uptight about extending her streak of never losing in the first round of a grand slam to 32 events.
"No, it was me," she said when asked what the German did to throw her off balance.
"I think she definitely played a tough game but I just think I made a lot of errors. I didn't feel I moved my feet well. I felt like I was just flat footed. I felt like I was just heavy. I don't know."
Williams had 38 winners to just 12 for the German, but she also committed more unforced errors -- 26 to 12 for Kerber.
Next up for Williams is unseeded Maria Elena Camerin of Italy, a 6-3 7-6 winner against Tatiana Poutchek of Belarus.
"I'll be fine," Williams added.
"If I do what I do in practice I'll be fine.
"If I play like I did today, I'm going to be in trouble."