Denly, 32, bats at number three for Kent but will open the innings in Antigua as a direct replacement for Jennings, who pays the price for a sequence of low scores and an average that has now dipped below 26.
Captain Joe Root announced the change on the eve of the second Test, with Jack Leach also recalled to a 12-man squad in place of Adil Rashid.
Denly made his first international appearance in almost a decade in a solitary Twenty20 win over Sri Lanka before Christmas, taking the man-of-the-match award predominantly for his four-wicket haul.
His leg-spin could also come in handy at the Sir Vivian Richards Stadium but it is at the top of the order that he will be expected to contribute most.
Root said at a press conference: “Joe is going to make his debut and open the batting.
“It’s disappointing for Keaton, he’s done some very good things and he’ll continue to keep developing.
“He’s very much a part of the squad moving forward but it’s a great opportunity for Joe.”
Leg-spinner Rashid has returned to England as his wife is expecting their second child. Left-arm spinner Jack Leach should find a spot in the playing XI with left-arm seamer Sam Curran likely to make way for Stuart Broad.
England 12-man squad: Rory Burns, Joe Denly, Jonny Bairstow, Joe Root (c), Jos Buttler, Ben Stokes, Moeen Ali, Ben Foakes, Sam Curran, Stuart Broad, Jimmy Anderson, Jack Leach
Provided by Press Association Sport
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