Ireland, who won the toss and chose to bat, scored 212-9 in their 50 overs, with newcomer Curtis Campher again top-scoring. England replied with 216-6 in 32.3 overs.
But after he departed at 131-4, Little also removed England skipper Eoin Morgan second ball without scoring and vice-captain Moeen Allie for a duck three balls later.
But there were no more breakthroughs and England made it home with 105 balls to spare.
Ireland were again slow to get going and lost their first four wickets for 44 runs in just 16 overs.
But they built partnerships after that with Harry Tector and Tucker putting on 34 runs for the fifth wicket and Campher and Simi Singh 60 for the seventh wicket.
Campher was eventually out for 68, getting a thick edge to Saqib Mahmood’s delivery and being caught in the deep by Adil Rashid.
The 21-year-old South African-born all-rounder, who qualifies to play for Ireland through an Irish grandmother, scored 59 not out on his ODI debut on Thursday, when England won the first game by six wickets.
There was also again a late flourish from Ireland’s No. 8 Andy McBrine who made 24, losing his wicket to the last delivery of the innings as Reece Topley finally got some reward on his return to the England team after a four-year absence.
Adil Rashid was the best home bowler with 3-34.
The last match of the series is again at Southampton.