The all-important goal came when Gabriel Heinze released Ronaldo down the left.
Ronaldo raced into the Boro box towards the byline and pursuing defender Jonathan Woodgate nicked his right leg to bring down the Portuguese winger.
Referee Mike Dean pointed to the spot and Ronaldo took two steps, stopped and then continued to run in to place the ball right-footed into the top-left corner of the net, sending Boro goalkeeper Mark Schwarzer the wrong way.
It was Ronaldo who had scored from the spot to level the scores at 2-2 when the teams first met at the Riverside Stadium nine days ago.
Ronaldo was also involved in a more controversial penalty decision when Boro manager Gareth Southgate accused him of diving to win a spot-kick in the Premiership match between the teams at the Riverside Stadium last December.
Louis Saha converted that penalty in a 2-1 win for the Reds, but Ronaldo is the undisputed spot-kick king for United.
The latest penalty seemed to irk Boro and substitute James Morrison was sent off two minutes into injury time for a wild lunge at Ronaldo.
For all their battling qualities, United goalkeeper Tomasz Kuszczak had only one save to make from the visitors - a 20-yard shot from Yakubu midway through the first half.
United had more half-chances than clear-cut opportunities, but the two best fell to Wayne Rooney.
On another day, Rooney would have comfortably tucked both of them away. This night saw him thwarted by two brilliant saves from Schwarzer.
The first came three minutes before the interval. Ryan Giggs threaded a glorious pass through the middle of the Boro defence for Rooney to run on to the ball.
The England striker raced into the box and looked favourite to round Schwarzer to score, but the Boro goalkeeper stood his ground and grabbed the ball off Rooney's toes.
The second chance came in the 70th minute. Michael Carrick's clever pass out of defence found Giggs and he produced another superb through ball to free Rooney just outside the Boro penalty area.
Rooney steadied himself before firing in a crisp right-foot shot only to see Schwarzer stick out his right leg to divert the ball behind for a corner.
Ronaldo also hit the outside of a post on the hour after running on to another excellent Carrick pass and beating Schwarzer with a shot from the right byline.
Boro's best chance came in the 55th minute when Stewart Downing collected a Mark Viduka pass in space 12 yards from goal but wastefully blasted his shot high over the bar.