Robbie Keane scored two goals, but the star of the show was fellow striker Dimitar Berbatov.
After a disappointing first-half performance, Middlesbrough gave a spirited display after the break but failed to avenge a 2-1 defeat at White Hart Lane in December.
Before the kick off there was a special ovation for Middlesbrough central defender Jonathan Woodgate, who signed a four-year contract for his home club earlier in the week.
Spurs made a good start with Keane on the mark after 12 minutes. Berbatov provided the pass and Keane the finish from just outside the six-yard box.
Spurs played the more skillfull football in the early stages with Berbatov given a free run.
Middlesbrough struggled to make an impact on the visiting defence and Paul Robinson had a quiet first half.
Berbatov was dangerous whenever in possession for Spurs and it was fortunate for Middlesbrough that Keane could not get to his cross from the right.
Spurs were holding the Middlesbrough strikeforce of Yakubu and Mark Viduka, though the latter shaved a post with a shot just before the break.
Middlesbrough manager Gareth Southgate introduced Adam Johnson five minutes before the interval.
Lee Cattermole was taken off but it was not clear whether the midfield player was injured or whether the substitution had been made for tactical reasons.
Two minutes after the break Spurs went two up when Hossam Ghaly provided a pass from the right and Berbatov struck a brilliant first-time shot from just outside the penalty area.
Goalkeeper Mark Schwarzer had no chance with the finish from a player who has proved an outstanding signing by the London club.
Keane was just wide after a one-on-one situation with Schwarzer as the goalkeeper rushed out to cut out the danger.
Middlesbrough began to play with more spirit and determination and from a Stewart Downing cross Viduka left Robinson helpless with a header for his 16th goal of the season.
Robinson brought off a fine save from Viduka and shortly after substitute Dong-Gook Lee shot wide.
Middlesbrough, who had been booed off at half-time by a section of the crowd, put everything into going for an equaliser.
Their hopes were dashed, however, when Keane scored his second goal seven minutes from time.
Substitute Aaron Lennon had only been on the field for 11 minutes when he provided the pass for Keane to score.
Middlesbrough stormed back with a header from defender Emanuel Pogatetz that reduced the arrears, but Spurs ran out winners to strengthen their UEFA Cup qualifying challenge.