The 27-year-old, who has suffered a string of injuries over the past few seasons, starts at 12 in the absence of injured Ben Te'o.
Elliot Daly is preferred at full-back to Mike Brown, who is left out of the 23-strong matchday squad.
George Kruis partners fellow Saracen Maro Itoje in the second row.
Owen Farrell starts at fly-half, with Henry Slade partnering Tuilagi in midfield and George Ford on the bench, while flankers Tom Curry and Mark Wilson make their first Six Nations appearances.
England have lost on six of their last seven Six Nations visits to Dublin, with a 12-6 victory in 2013 their most recent success.
Ireland, who beat world champions New Zealand in November, are ranked second in the world, two places higher than their visitors.
"It is well documented no-one thinks we can win," head coach Eddie Jones said. "But I can tell you everyone inside our camp believes we can win. We are hugely looking forward to the weekend."
Tuilagi has made only two replacement appearances for England since starting England's defeat by New Zealand in Hamilton in June 2014.
During that time, he has been sidelined with chest, knee and hip problems, but has made an impressive return for Leicester this season, scoring six tries in 14 appearances for the Tigers, and gives England a powerful ball-carrying option in midfield.
"I just felt for this game the best option was to play Owen Farrell at 10 and Manu as a like-for-like replacement for Ben Te'o," Jones said.
"Manu has impressed us at the training camp, and is right to play."
Ireland's aerial game has been a feature of their rise to second in the world rankings and England have been stung before with Robbie Henshaw scoring the only try of the 2015 meeting after claiming a kick over the head of full-back Alex Goode.
Jones said his side are well aware of the dangers, despite the selection of Daly over specialist 15 Brown.
"I think it is quite clear to beat Ireland you have to beat them in the contest area. They are very good at the breakdown and in the air," he added.
"Both those areas are a priority for us.
"Browny is a great player and we are always looking at how we can improve the team but, at the moment, we believe that Elliot is the best 15 for us. He can do the job for us and gives us a great attacking game."