It is thought Henderson has left after failing to deliver the expected growth in William Hill's online business. A statement from the board gave little further detail about his departure.
He has been replaced for the interim by chief financial officer Philip Bowcock, whose priorities lie in turning around the brand's online business.
Henderson, formerly operations director, took the helm two years ago when his highly successful predecessor, Ralph Topping, retired. But the business has come under pressure from consumer preference for online gambling and consolidation in the market.
Paddy Power merged with online powerhouse Betfair earlier this year, while Ladbrokes and Coral are also planning to combine.
Chairman Gareth Davis said of the new interim chief executive: "Philip has a clear set of priorities as interim CEO, principally the continued turnaround of the online business.
"We will confirm a successor in the coming months."
William Hill restructured its online team earlier this year, with the promotion of corporate development and innovation director Crispin Nieboer to online managing director in May. Nieboer replaced Andrew Lee, who departed the company in January. Director of innovation and customer experience, Jamie Hart, also left in March.
The company will publish its results for the first half of the year next month. In its May trading update, the company reported a decline in net revenue online of 11% in the four months to 28 April. Overall revenue slumped after the victory of Leicester City and punters cashed in on bets made during Cheltenham Festival.
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