Mirjana Lucic-Baroni, ranked at 70 in the world and who had also defeated 2014 Roland Garros runner-up Halep in the US Open last year, goes on to face France's Alize Cornet.
By defeating US top seed Venus Williams, Croatia's Mirjana Lucic-Baroni ended the longest gap between titles in WTA history, a wait of 16 years and four months.
Second seed Simona Halep lost 6-7, 2-6 against Mirjana Lucic-Baroni in the third round. Lucic-Baroni last experienced such a deep run at a major at Wimbledon in 1999 when she reached the semi-finals.
Seventh-seeded Francesca Schiavone needed just 53 minutes to advance to the third round of the US Open, beating Mirjana Lucic 6-1, 6-1 on Thursday.
Ana Ivanovic reached her first semifinal since October by beating Mirjana Lucic 6-3, 6-4 at the Aegon Classic on Friday.
Maria Sharapova eased into the Roland Garros second round on Tuesday, but the Russian took second billing to grieving Virginie Razzano, who honoured her fiance's dying wish to play the French Open.