The 25-year-old Gesink snatched the leader's yellow jersey after winning the gruelling 126 kilometres (78 miles) mountain climb from Ontario to Mt Baldy in three hours 37 minutes and eight seconds.
He started the day in third place, 38 seconds behind the overall leader, American David Zabriskie, but ended up leading by a commanding 46 seconds with only the short final stage in Los Angeles to come.
"I'm back," said Gesink, who broke his leg in a crash last year.
"I've been working really, really hard the last months. It didn't always work out in the beginning and that's difficult on an athlete, always wanting to win.
"Now to be back at the highest level and to be the best uphill like this is unbelievable."
Zabriskie remained second overall while Tom Danielson of the US moved into third place after finishing seventh in the stage.
John Atapuma of Colombia was second in Saturday's stage, in the same time as Gesink, after leading most of the day. His Countryman Fabio Duarte crossed the line, 14 seconds later.
Last year's winner, American Chris Horner, joined Atapuma in the lead after joining a breakaway group. But he was unable to keep up and faded to finished sixth and, rising to eighth overall.
“I had a nice victory over here four years ago, and I am really happy to be back at this level after a difficult year," said Gesink.
“I lost my dad a bit more than a year ago, and felt dead myself. Emotionally it was a really difficult year, and now to be back at the highest level, it's incredible."