Defoe helped himself to a brace at the National Hockey Stadium and Mido bagged a double before sub Robbie Keane sealed the rout at the death.
Milton Keynes, without the transfer-listed Ben Chorley, who had been dropped from the squad altogether, had actually started brightly and only a perfectly timed last-ditch sliding tackle in the box by Spurs centre-half Anthony Gardner prevented Izale McLeod going through one-on-one in the first
But Spurs soon settled into their stride and Defoe forced transfer-listed Dons' goalkeeper Adolfo Baines into a good save from 20 yards before Mido broke the deadlock with a neat 35th minute finish.
Reto Ziegler was afforded time and space by Dons' full-back Jamie Smith to whip in a dangerous low cross that Mido swept in first time at the near post from five yards.
At the other end, McLeod skinned Calum Davenport down the left but his low angled drive was saved comfortably by Spurs' back-up keeper Radek Cerny at the near post.
And Defoe showed him how it should be done by doubling Tottenham's lead two minutes before the break with a cool one-on-one finish.
Mido was given acres of space to run at the Dons' defence and slot the pacy England striker clean through, who cleverly lifted the ball over the on-rushing Baines and into the net.
The impressive Dean Lewington curled a 35-yard free-kick inches wide for the Dons three minutes after the re-start, but Defoe clinically put Spurs 3-0 up in the 51st minute.
The former West Ham striker latched on to Tom Huddlestone's cheeky scoop over the Dons' defence and crisply slotted his second goal of the game low past Baines from ten yards.
Mido completed his brace to make it 4-0 in the 59th minute, ramming in the rebound from close range after Defoe's angled drive had been saved by Baines.
The Dons battled back in the closing stages, but Aaron Wilbraham's half-volley was tipped over by Cerny and McLeod fired against the post, before Spurs sub Keane sealed the rout in the 90th minute, superbly half-volleying Drissa Diallo's poor back-header past Baines from 12 yards.