The company said Tuesday that Chairman Ed Whitacre Jr. will serve as interim CEO. The company plans an international search for a new president and chief executive.
At a press conference here, Whitacre read a brief statement thanking Henderson for his work during a period of challenge and change.
Henderson, 51, succeeded Rick Wagoner on March 29 after the Obama administration ousted GM's former CEO as the company worked through a government-led reorganization.
Henderson spent the next few months working with the government to reorganize the automaker outside of bankruptcy, but eventually took the company into bankruptcy protection in June.
With the government's help, the company emerged from court protection in just 40 days cleansed of massive debt and burdensome contracts that would have sunk it without federal loans.
Henderson continued to downsize the automaker after its emergence from bankruptcy. He sought to scale down GM to just four core brands: Chevrolet, Cadillac, Buick and GMC.
While he has largely succeeded in that goal, attempts to sell the company's other brands have hit obstacles.
The company is winding down Pontiac and was successful in winning a tentative sale of Hummer to a Chinese construction machinery maker.
However, Henderson's bid to sell Saturn to racecar mogul Roger Penske fell through and the brand is now liquidating. Last week, Swedish sports car maker Koenigsegg Automotive AB dropped out of a deal to buy Saab.
Earlier Tuesday, GM said it will phase out its storied Swedish Saab brand if no deal is reached by the end of this month.
GM's board met Tuesday to decide Saab's fate after a group led by Sweden's Koenigsegg Automotive ABlast week to buy the company. About 4,500 jobs at Saab are at stake.
New potential buyers have emerged, GM said, so the board put off a final decision until the end of December. The automaker said in a statement that no "suitable arrangement" for Saab is found by then, it would "will begin an orderly wind down" of the unit.
GM would not identify the potential bidders. Last week, the Chinese company Beijing Automotive Industry Holdings said it would re-evaluate Saab, but stopped short of saying it would make an independent bid. Beijing Automotive had been part of the Koenigsegg team.
The private equity firm The Renco Group Inc. and the investor group Merbanco Inc. have reportedly also been interested in Saab.
The failed Saab sale marks the third time this year that GM couldn't close a deal for an unwanted brand that it is shedding as part of its reorganization.
GM decided to close Saturn after a deal with auto dealer Roger Penske fell through. And the automaker's board decided to keep the European automaker Opel after deciding it was too heavily integrated into the company for GM to let it go.