With the half-time whistle approaching, Osula broke the deadlock on his 100th senior outing after reacting to Lewis Miley's cross from the right flank before poking the ball beyond Palace goalkeeper Dean Henderson.
United, however, found themselves level in the 80th minute as Mateta, introduced from the bench, headed home from close-range after a dangerous attack from the hosts before the Frenchman netted from the penalty spot in stoppage-time after Sven Botman was adjudged to push Jefferson Lerma inside the box.
Sandro Tonali, Miley, Malick Thiaw, Tino Livramento, Jacob Murphy and Osula all returned to the line-up ahead of facing Oliver Glasner's men, who claimed a 3-0 win against Fiorentina in Thursday's UEFA Conference League quarter-final first leg.
Newcastle will be aiming to complete a league double over the Eagles since the 2013/14 campaign, with United claiming a 2-0 win in January's reverse fixture at St. James' Park following second-half goals from Bruno Guimarães and Thiaw.
Today's clash is the 50th league meeting between the two sides, with the Magpies targeting a first win at Selhurst Park since November 2020 as late strikes from Callum Wilson and Joelinton sealed a 2-0 triumph in South London.
**Newcastle United:** Aaron Ramsdale, Lewis Hall, Sven Botman, Joelinton (Jacob Ramsey 84), Sandro Tonali, Anthony Gordon (Harvey Barnes 71), Malick Thiaw, Will Osula (Nick Woltemade 84), Tino Livramento, Jacob Murphy (c), Lewis Miley.
**Subs not used:** Nick Pope, Kieran Trippier, Yoane Wissa, Anthony Elanga, Joe Willock, Dan Burn.