Liverpool edged League One Crewe 2-1 but West Ham and Fulham were the victims of third-round upsets. The Hammers lost 1-0 at Watford and Fulham went down 1-0 at Burnley.
With the Premier and Champions Leagues to think about, the top clubs fielded many of their young stars in the race for the third most important title in English football.
But Ronaldo had been sidelined for three months because of an ankle injury and, after two appearances as a substitute, marked his first start by heading home a corner by Ryan Giggs in the 25th minute against Middlesbrough at Old Trafford.
After Adam Johnson's 56th-minute deflected shot levelled for Boro, teammate and defender Emmanuel Pogatetz was sent off for a foul that led to lengthy treatment for United forward Rodrigo Possebon. Ryan Giggs then punished a blunder by Chris Riggott to put United back in front in the 70th, and Nani added the third in injury time.
Vela scored three and Nicklas Bendtner two as Arsenal crushed Sheffield United 6-0 despite resting most of its stars and fielding mostly teenagers at Emirates Stadium. The average age of the outfield players was 18.
The Gunners' backup players reflected the quality of their first-choice stars by mesmerizing the League Championship team with their passing skills, and the Blades were lucky to concede only six. Jack Wilshere, age 16, netted the other Arsenal goal.
After Daniel Agger put Liverpool ahead in the 15th minute with a free kick, Michael O'Connor threatened an upset with an equalizer for Crewe 10 minutes later at Anfield. But Brazilian star Lucas header the winner in the 58th.
Watford upset Gianfranco Zola's West Ham 1-0 after Hammers defender Hayden Mullins deflected the ball into his own net in the 70th.
Fulham was ousted 1-0 by another League Championship club, Burnley, whose matchwinner was substitute Jay Rodriguez in the 88th, only two minutes after entering the game and on only his second appearance for the club.
Sunderland and Stoke needed to win penalty shootouts to reach the last 16 after 2-2 draws with teams from the lower divisions. Sunderland hit back from two goals down against League One Northampton, Anthony Stokes scoring his second goal in injury time, and then beat the Cobblers 4-3 in a shootout after extra time.
Stoke twice threw away the lead against League Championship Reading for a draw after extra time and then won the shootout 4-3.
Six more games are on Wednesday including defending champion Tottenham, last in the Premier League standings, against next-to-last Newcastle.