Sixth seed Kerber was defeated 6-3, 6-1 by Japanese teenager Naomi Osaka, becoming the first defending champion in New York to exit in the opening round since Svetlana Kuznetsova suffered a similar fate in 2005.
The German left-hander became number one for the first time after winning the 2016 US Open title, but she handed it back to Serena Williams when the American star won the Australian Open in January.
In March, and with Williams off the tour to prepare for the birth of her first child, Kerber went back to the top only to lose it again to Karolina Pliskova after Wimbledon.
"I think because it's a new situation," said the 29-year-old when asked why it was so hard for her to cement her place on top of the rankings.
"Of course, you have always the goal for years of reaching the top, but then if you are there, you actually don't know what to expect, and then it's just the process.
"You have to get used to everything. You have to schedule your day, plan completely different and it's for sure tougher staying on top."
In 2017, Kerber made only the last 16 at the Australian Open and Wimbledon with a first-round exit at the French Open sandwiched in between.
Her build-up to the US Open was then hampered by an elbow injury with a round of 16 run in Toronto followed by an opening defeat against Ekaterina Makarova in Cincinnati.
Kerber's loss to Osaka also means she will slip out of the world's top 10.
It also left her without a title since her 2016 US Open triumph and highlighted the struggles of a batch of players trying to fill the power vacuum left by Williams's pregnancy, Victoria Azarenka's recent maternity leave and Maria Sharapova's 15-month doping ban.
At the start of the US Open, eight women were in contention to be world number one at the end of the fortnight.
One of those, Britain's Johanna Konta, lost on Monday and dropped off the list.
In another indication of the vagaries of the world number one pursuit, second-ranked Simona Halep could take spot even though she was knocked out of the tournament by Sharapova in Monday's first round.
Pliskova, meanwhile, stayed on course to preserve her status by seeing off Magda Linette of Poland on Tuesday, but the 2016 runner-up has yet to win a major.
"It's not something I want to think about on the court," said the 25-year-old Czech.
"Maybe off the court, obviously I would like to stay there as long as I can, but not to push it and I don't want to stress myself because of this and then play.
"But I believe if I play good tennis, I have a good chance to stay there."
The German left-hander became number one for the first time after winning the 2016 US Open title, but she handed it back to Serena Williams when the American star won the Australian Open in January.
In March, and with Williams off the tour to prepare for the birth of her first child, Kerber went back to the top only to lose it again to Karolina Pliskova after Wimbledon.
"I think because it's a new situation," said the 29-year-old when asked why it was so hard for her to cement her place on top of the rankings.
"Of course, you have always the goal for years of reaching the top, but then if you are there, you actually don't know what to expect, and then it's just the process.
"You have to get used to everything. You have to schedule your day, plan completely different and it's for sure tougher staying on top."
In 2017, Kerber made only the last 16 at the Australian Open and Wimbledon with a first-round exit at the French Open sandwiched in between.
Her build-up to the US Open was then hampered by an elbow injury with a round of 16 run in Toronto followed by an opening defeat against Ekaterina Makarova in Cincinnati.
Kerber's loss to Osaka also means she will slip out of the world's top 10.
It also left her without a title since her 2016 US Open triumph and highlighted the struggles of a batch of players trying to fill the power vacuum left by Williams's pregnancy, Victoria Azarenka's recent maternity leave and Maria Sharapova's 15-month doping ban.
At the start of the US Open, eight women were in contention to be world number one at the end of the fortnight.
One of those, Britain's Johanna Konta, lost on Monday and dropped off the list.
In another indication of the vagaries of the world number one pursuit, second-ranked Simona Halep could take spot even though she was knocked out of the tournament by Sharapova in Monday's first round.
Pliskova, meanwhile, stayed on course to preserve her status by seeing off Magda Linette of Poland on Tuesday, but the 2016 runner-up has yet to win a major.
"It's not something I want to think about on the court," said the 25-year-old Czech.
"Maybe off the court, obviously I would like to stay there as long as I can, but not to push it and I don't want to stress myself because of this and then play.
"But I believe if I play good tennis, I have a good chance to stay there."
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