Out-of-contract pair Ashley Fletcher and Britt Assombalonga will not play for Middlesbrough again this season.
Assombalonga, 28, cost a club record £17m to sign from Nottingham Forest in July 2017, while Fletcher, 25, joined from West Ham for £6m.
Speaking after Wednesday's 2-1 win at Rotherham, boss Neil Warnock said he "just felt the time was right".
"We've only got four games left," he added. "I just felt it was the right time to involve some of the youngsters."
The decision has been taken after a five-match run without a win ended Boro's slim chances of finishing in the Championship's play-off spots.