But Boro captain Gareth Southgate conceded a spot-kick 10 minutes from time, and Gex Murphy stepped up to send Boro's rookie goalkeeper Brad Jones the wrong way.
Liverpool looked set to be exiting the competition as they trailed Luton 3-1 at Kenilworth Road, but hit back to win 5-3 - with Xabi Alonso scoring two with stunning long-range strikes.
Veteran Newcastle striker Alan Shearer hit his 200th goal for the club in the 1-0 win over Mansfield, matching record Magpies goalscorer Jackie Milburn's haul.
But his goal will do little to relieve the pressure on manager Graeme Souness, as his side struggled to impose themselves on the visitors from League Two.
League One side Huddersfield were dreaming of a replay with Premiership champions Chelsea, when Gary Taylor-Fletcher drew them level at Stamford Bridge.
Carlton Cole had put the home side ahead with an early goal, and the Yorkshire side's hopes of another chance at their illustrious opponents was ended when Eidur Gudjohnsen struck with eight minutes to go.
Robbie Fowler's hat-trick put Manchester City through at the expense of the Scunthorpe, after Andy Keogh had put the Iron ahead.
Premiership Birmingham are lucky to still be in the competition, after a goalless draw with League Two strugglers Torquay United - who had a goal disallowed and saw an effort rattle off the woodwork - at Plainmoor.
Debutant Marvin Williams thought he'd earned Millwall the scalp of Everton with a classy first-half strike.
But the 18-year-old's goal was cancelled out by a Leon Osman header which spared the Toffees' blushes.
Conference side Tamworth forced a replay against their Staffordshire neighbouts Stoke after a goalless draw at the Britannia Stadium
Blackburn were comfortable 3-0 winners over QPR, while Charlton overcame stiff Sheffield Wednesday resistance to win 4-2 at Hillsbrough.
Dario Silva's strike edged Portsmouth past Ipswich at Portman Road, with Bolton were also 3-0 victors at Watford.
Holders Arsenal eased past Cardiff 2-1 at Highbury. Gareth Barry's second-half strike was enough to seal Aston Villa's 1-0 win over Hull at the KC Stadium.
Rob Hulse earned Championship side Leeds a replay with Wigan, with his late goal levelling David Connolly's early strike.
Reading and West Brom must replay their tie after a 1-1 draw at the Hawthorns, while West Ham were comfortable 3-0 winners over Norwich at Carrow Land - in a match more noteable for an injury to Canaries goalkeeper Rob Green, prompting seven minutes of time added on at the end.
Championship side Sheffield United, who are clear at the top of the League table along with Reading, were knocked out with a 2-1 home loss to League One side Colchester.
Former Scunthorpe midfielder Richard Kell made his debut for Barnsley as a late substitute in their 1-1 draw with Walsall, with fellow ex-Iron Paul Hayes scoring their goal.