Federer, the 2009 champion and bidding for an 18th major, tackles Indian qualifier Somdev Devvarman, the world number 188.
Second seed Federer beat Devvarman in their only previous meeting in straight sets in Dubai in 2011.
Williams, the defending women's champion, faces French teenager Caroline Garcia who was a set and 4-1 up on Maria Sharapova at Roland Garros in the second round in 2011 before losing in three.
The American top seed is looking for a second title in Paris, 13 years after her first.
Australian Open champion Victoria Azarenka, the third seed, faces experienced Russian Elena Vesnina in a first round match held over from Tuesday because of rain.
Court Philippe Chatrier also hosts two of France's best hopes of ending a 30-year wait for a home men's champion.
Sixth seed Jo-Wilfried Tsonga plays veteran Finn, Jarkko Nieminen, while wildcard Gael Monfils, who put out fifth seed Tomas Berdych in the first round, comes up against in-form Latvian, Ernests Gulbis.