Evelyn Webster, the former executive vice president at Time Inc, will take over in an interim role and begin the search for a new chief executive.
Store joined The Guardian in 2014, leaving MEC as president of agency development in New York.
Webster left Time Inc in August 2016 after five years. In the new role she will lead the commercial and operations teams and work with US editor Lee Glendinning to help the title "focus on rebalancing its core business model to ensure it is able to serve its loyal and growing readership".
Before Time Inc, Webster was at IPC Media for 18 years, having joined as a graduate trainee in 1992. When she left she was the chief executive.
Webster will report to David Pemsel, chief executive at Guardian Media Group. Pemsel said: "Eamonn has led the US business with passion and dedication at a time of huge volatility across the industry, and I’d like to thank him for all his hard work and many achievements.
"I am also delighted to have attracted someone of Evelyn’s calibre and experience, on an interim basis, to work closely with Lee Glendinning, the editor of Guardian US, and the senior team on the ongoing transformation of our US operations and our continued focus on maximising the enormous opportunities for Guardian journalism in the US market."
Before joining the publisher, Store worked across several agencies including Starcom Mediavest Group, Profero, and Carat. He will depart Guardian US later this month.
He said: "As the digital news market continues to evolve at speed I’m incredibly proud of what we have achieved at Guardian US over the last three years, including the doubling of our overall audience and significantly increasing our overall revenue.
"Now feels like the right time to hand over the reigns as I explore the next chapter of my career in an area I am passionate about, working to help senior corporate leaders drive stronger corporate citizenship by developing deeper, more enduring cause related partnerships with those dedicated to doing good in this world."
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