Uruguay were already operating without Luis Suarez and Diego Godin, and Oscar Tabarez's experimental line-up was unsettled by the early withdrawal of Cavani, who decided he was unable to continue shortly after a collision with Kevin Long.
Ireland were good value for taking the lead before the half-hour mark, when Walters finished superbly from 20 yards, but the Stoke forward went from hero to villain in first-half stoppage time when, after Atletico Madrid defender Jose Gimenez headed an equaliser, he hit the crossbar from close range with the goal gaping.
There was an element of fortune about the hosts' second goal when a cross-cum-shot from Derby County full-back Christie skidded low into the corner but victory was sealed emphatically on the break by substitute McClean 13 minutes from time.
It meant Martin O'Neill's men bounced back impressively from losing by the same scoreline against Mexico two days ago and enjoyed a timely confidence boost ahead of their final World Cup qualifier of the season against Austria.
Visiting goalkeeper Esteban Conde was making his international debut at 34 and saved well as Uruguay waited to introduce Middlesbrough's Cristhian Stuani as Cavani's replacement, palming behind from Robbie Brady.
But Conde was in no man's land as he flapped at the resulting corner, with Shane Duffy just unable to find the decisive touch.
Uruguay were struggling for fluency without their attacking focal point and fell behind in the 27th minute.
Walters collected a pass from Stoke team-mate Glenn Whelan and, with the help of some hesitant defending on the edge of the Uruguay box, Ireland's captain lashed a brilliant shot into the top corner.
Martin Caceres headed a 34th-minute corner against the bar for the South Americans and Ireland did not heed that set-piece warning, with goalkeeper Darren Randolph venturing errantly from his line before Gimenez's effort looped in.
Walters should have restored the hosts' lead in first-half stoppage time but inexplicably fired against the bar from two yards after Brady left him with the goal at his mercy.
Thankfully for the experienced forward, he would not have to dwell on the miss for too long as right-back Christie cut inside Caceres and clipped a left-footed effort into the far corner.
Stuani fell foul of the Ireland offside trap when he netted midway through the half, while Gimenez was denied a second when he again towered above the home defence but saw Randolph's half-time replacement Keiren Westwood save brilliantly to his left.
Uruguay must hope to muster more enthusiasm for their midweek trip to Italy than they showed here and Gimenez endured a more forgettable involvement in the 77th minute - diving in desperately and unable to halt McClean on the end of Daryl Murphy's thoughball, with the West Brom winger streaming clear to lash home across Conde.