Defoe was keen to impress the watching England manager Sven-Goran Eriksson and stole all the headlines once again with an unstoppable shot in the second half to help Spurs claim a convincing victory.
Mido added a second when his shot was fumbled by Mark Schwarzer in the Middlesbrough goal and helped make up for the heartache of missing out on a UEFA Cup spot last season and put them top of the Premiership.
Edgar Davids made an immediate impression at the heart of the Spurs midfield inside the opening 60 seconds when he clashed with Ray Parlour and the ex-Arsenal midfielder fell to the ground - much to the joy of the home supporters.
Tottenham created their first chance after five minutes when Paul Stalteri's cross fell for Teemu Tainio whose header produced a fine save from Schwarzer.
Stewart Downing was keen to impress in front of the watching England coach Eriksson and provided a pin-point cross for Jimmy Floyd Hasselbaink on 13 minutes, but his header flew just over the bar.
Downing was involved in the heart of the action on 19 minutes when his inswinging corner eluded everyone inside the box.
The ball fell to Hasselbaink at the far post, but the Dutch striker failed to direct his header towards goal.
Davids almost capped his Premiership debut with a goal on 21 minutes when Mido's cross picked out the Dutch superstar inside the box, but his overhead kick produced an easy save from Schwarzer.
Davids then turned provider on 25 minutes when his ball picked out Tainio on the edge of the box.
The Finnish international cleverly back-heeled the ball into the path of Michael Carrick, who struck a fierce 30-yard drive which flew inches over the crossbar.
Tottenham had strong claims for a penalty turned down on 36 minutes when Jermain Defoe's shot appeared to hit the hand of Matthew Bates, but referee Atkinson waved for play to continue.
Middlesbrough came close to breaking the deadlock again on the stroke of half-time when Downing's corner caused all kinds of problems for the Spurs defence.
The ball fell to Yakubu, who was well placed in the penalty box but he struck the ball just over the crossbar.
Hasselbaink could have made it a dream start for Boro just two minutes into the second half when he lifted the ball over Paul Robinson, but the ball fell inches over the bar.
And they were made to pay for that missed opportunity when Defoe opened the scoring in spectacular fashion on 49 minutes.
Tainio's ball picked out Defoe just inside the Middlesbrough half. The England striker raced towards the penalty box before unleashing an unstoppable shot which sailed past Schwarzer into the corner of the net.
Downing was desperately unlucky not to pull Middlesbrough level on 54 minutes.
The England winger fired a sweet curling free-kick which produced an excellent save from Robinson diving away to his right.
And it was Mido who wrapped up all three points for the home side on 76 minutes when his weak shot from the edge of the box was somehow fumbled by Schwarzer and the ball crept into the back of the net.
Jermain Defoe made up for his England misery by firing an unstoppable shot to set Spurs on their way to a convincing victory.