Before this year, the earliest exits suffered by a top seed were in the second round — Justine Henin in 2004 and Serena Williams in 2014.
Makarova goes on to face either Lesia Tsurenko or Kateryna Kozlova, both of the Ukraine.
— Roland-Garros (@rolandgarros) May 28, 2017
“It’s unbelievable to win and to do it on my first appearance on Philippe Chatrier court as a singles player after nine years of coming to Paris,” said Makarova, a former semi-finalist at the Australian and US Opens.
“At the end of the match, it was really tough as I knew she wouldn’t give it to me — I had to win it.”
It was the second successive first round exit at Roland Garros for world number one Kerber, the reigning US Open champion.
Last year, she fell to unseeded Kiki Bertens of the Netherlands.
It also continued a miserable spell for the German 29-year-old on clay this year.
She lost her opener in Stuttgart where she was the defending champion, suffered a thigh injury in the third round in Madrid and lost first time out in Rome.
On Sunday, she fell a double break down to trail 5-1 to her Russian opponent who she was facing for the 12th time.
Makarova, now ranked 40 after reaching a career high of eight, was a double break ahead again for 3-0 in the second set.
Four successive breaks of serve followed before Makarova saved seven break points in the crucial eighth game to cause the upset.