Leinster winger Lowe, 28, was born in New Zealand but has qualified for the men in green through residency and his first game will be against Wayne Pivac’s side.
Lowe starts alongside Hugo Keenan and Jacob Stockdale in the back three.
Lowe’s Leinster team-mate Jamison Gibson-Park, another man born in New Zealand, makes his first start at scrum-half.
Ulster fly-half Billy Burns is in line to make his debut from the bench.
“He brings an extra dimension to how we want to play,” Ireland head coach Andy Farrell said of Lowe.
“Hopefully, on top of that, with a good performance at the weekend, he brings another dimension of competition for places in our squad which is very important for us going forward.”
Ronan Kelleher returns from injury to start at hooker alongside props Cian Healy and Andrew Porter.
Ulster captain Iain Henderson comes back into the side after serving a suspension to start in the second row with James Ryan.
Caelan Doris retains his spot in the back-row and will pack down at No 8 along with flankers Peter O’Mahony and Josh van der Flier.
Gibson-Park’s debut provides Farrell with a new all-Leinster half-back axis with skipper Johnny Sexton while Robbie Henshaw will partner Chris Farrell at centre.
Ireland side to face Wales: Jacob Stockdale; Hugo Keenan, Chris Farrell, Robbie Henshaw, James Lowe; Jonathan Sexton (captain), Jamison Gibson-Park; Cian Healy; Ronan Kelleher, Andrew Porter, Iain Henderson, James Ryan, Peter O’Mahony, Josh van der Flier, Caelan Doris
Replacements: Dave Heffernan, Ed Byrne, Finlay Bealham, Quinn Roux, Will Connors, Conor Murray, Billy Burns, Keith Earls
