Denly, 34, was initially set to play in the series opener at The Ageas Bowl on Thursday - which England won by six wickets - but suffered back spasms in training the day before and was replaced in the XI by Kent team-mate Sam Billings, who went on to score an unbeaten 67. England were without a number of regulars who are preparing for the Test series against Pakistan next week, but returning seamer David Willey had Ireland in early trouble as he picked up career-best figures of 5-30 in a fine display of swing bowling.
England's Joe Denly has been ruled out of the ODI series against Ireland through injury with Liam Livingstone taking his place.
The three-match one-day global series at Southampton's Ageas Bowl launches the new World Cup Super League, which will determine qualification for the 2023 50-over World Cup in India. But Billings and captain Eoin Morgan (36 not out), a former Ireland global, put on 96 for the fifth wicket to secure victory with 22.1 overs to spare. The toss will take place at 6:00 PM IST.
Ireland were in danger of being dismissed for under 100 but all-rounder Curtis Campher held firm with an unbeaten 59 on debut. He put on 66 for the eighth wicket with Andy McBrine (40) to give Ireland something to defend.
In England's first home one-day worldwide since being crowned world champions, Willey bowled with plenty of guile and was chiefly responsible for Ireland teetering to 28 for five in the seventh over.
Ireland were 7-2 when skipper Andy Balbirnie was caught behind driving at Willey.
It got even better for Willey when Gareth Delany sliced to backward point to end a counter-attacking 22 while Lorcan Tucker departed next ball, lbw after a review showed the delivery would have crashed into leg stump.
The players on both sides took a knee in support of Black Lives Matter - as was the case during England's Test series against the West Indies - before Willey made inroads into the batting line-up with just his fourth delivery.
Where will the England vs Ireland 1st ODI be played?
England's red and white-ball fixtures are overlapping in a season cut short by the coronavirus outbreak and they are maintaining two separate squads, meaning a clutch of World Cup winners including Joe Root and Ben Stokes will not feature against Ireland.