The route, which was reportedly brought back following "huge customer demand" will open up the west of Ireland to southern England.
It was previously operated by other airlines before being suspended in autumn last year.
XL Airways will be the only carrier to fly from Gatwick to Ireland West Knock and will offer connections six times a week, rising to seven a week from May 2008.
Martin Lock, managing director of XL.com, said: "We introduced the Gatwick-Knock route as a response to huge customer demand following other airlines pulling out last year.
"Gatwick is London's main leisure airport and is only 30 minutes away from central London on the Gatwick Express - getting to Knock has never been easier!"
West and north-west Ireland offer a number of attractions to visitors, including Roman Catholic Marian shrines, the coast of Mayo and historical Roscommon.
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(Tony Hill and Helen Gillilan)
