The veteran striker, who played under McClaren at Middlesbrough, came off the bench to fire in a late winner for the Royals and take Steve Clarke’s Championship side into the FA Cup quarter-finals.
Derby had played much of the game with 10 men following Stephen Warnock’s first-half sending-off but when Darren Bent found an equaliser to cancel out Hal Robson-Kanu’s opener, a replay looked likely.
But Clarke turned to Yakubu and the Nigeria international scored with one of his first touches to take Reading through to the last eight and just one win away from a trip to Wembley.
Derby had started the game much the brighter with Craig Bryson testing Reading goalkeeper Adam Federici in the opening minute of the match.
There were further efforts on target from Simon Dawkins, Bent and Jesse Lingard as McClaren’s in-form team looked to be playing with plenty of confidence despite several players being rested.
Reading always carried a threat and Simon Cox might have done better than blast the ball at Kelle Roos following a clever free-kick routine.
That set-piece came as a result of an aggressive challenge by Warnock and the experienced full-back ought to have realised that required a more cautious approach thereafter.
Instead he charged into Jamie Mackie and duly received a second yellow card from referee Craig Pawson.
While that decision angered the home support, Derby were fortunate not to see a penalty awarded against them when a Danny Williams shot struck skipper Richard Keogh on the arm.
Reading were not to be denied though and took the lead early in the second half when Robson-Kanu finished brilliantly with his left foot to complete a flowing move down the right flank.
That might have been that but Derby continued to play their football despite being a man down and were rewarded with an equaliser eight minutes later courtesy of Bent.
Lingard found space inside the box and looked set to convert a low cross from the left but he sliced his effort and the ball diverted off the legs of Bent and into the Reading net.
With neither team playing for a replay it was end-to-end stuff as substitute Jamie Ward added fresh impetus for the home side.
Pavel Pogrebnyak looked to have wasted the best chance to win the tie for the away team when he failed to beat Kelle Roos with his head from point-blank range with 20 minutes to go.
Clarke had seen enough by that point and sent for Yakubu to replace the Russian in attack and it didn’t take long for the Reading fans to bring out the ‘feed the Yak and he will score’ chants.
The visitors broke quickly and found themselves in a two-on-two situation and when the ball was threaded through to Yakubu he finished expertly to sweep the ball beyond Roos and win the match for his team in only his second appearance for the club.