Rob Kearney, James Ryan and Kieran Marmion will play no part in Ireland's final autumn international against the USA on Saturday.
The trio started last weekend's win over New Zealand and are among seven players to be released by Joe Schmidt.
Sean Cronin, Jack McGrath, Dan Leavy and Jordan Larmour are also returning to Leinster.
Peter O'Mahony is an injury concern having suffered a dead leg against the All Blacks.
Leavy, initially named at openside flanker before a neck strain ruled him out of the New Zealand Test, will continue his rehabilitation at Leinster.
Schmidt is likely to name a much-changed side including players who have not seen regular action so far in November.
Ulster's John Cooney could start at scrum-half having deputised for Luke McGrath against Italy in Chicago and missed out on a place in the squad for the games against Argentina and New Zealand.
Ross Byrne is in line for a first international start alongside Cooney at 10 while Stuart McCloskey, Darren Sweetnam and Sam Arnold are among the other players hopeful of receiving some gain time.
With Schmidt's first-choice picks seemingly set in most positions, the USA game is likely to present an opportunity for players to stake a claim for a regular squad space as Ireland head towards a World Cup year on the back of a remarkable 2018.