Defoe looked back to his very best and must surely be knocking on the door for a recall to the England side after impressing the watching Sven-Goran Eriksson.
The latest victory for Spurs means they have enjoyed their best winning run since 1995 when Gerry Francis was in charge of the side.
Tottenham opened the scoring after just seven minutes. Michael Carrick's superb ball upfield released Fredi Kanoute who raced clear of the Southampton defence.
He cleverly cut the ball back for Defoe, who made no mistake in firing the ball past Antti Niemi in the Saints goal.
Southampton could have equalised on 15 minutes. Kevin Phillips' deflected shot flew just over the crossbar.
From the resulting corner, Anders Svensson saw his close-range header fly inches past the post.
Carrick produced another excellent piece of skill on 17 minutes when he turned two Southampton defenders and drilled a low powerful drive which brought a fine save from Niemi.
Defoe should have grabbed his second of the game on 26 minutes after Michael Brown's pass released him clear into the penalty box, but the England striker fired his shot straight at Niemi.
However, Defoe wasted no time making up for his miss when he scored Tottenham's second just 60 seconds later.
Paul Telfer stuck his leg out and gifted the ball to Defoe inside the area who broke the offside trap and coolly slotted the ball past Niemi into the corner of the net.
Kanoute was desperately unlucky not to add a third on 37 minutes when his 25-yard shot was superbly pushed away by Niemi diving away to his left.
But the Mali international finally got his just rewards on the stroke of half-time after Carrick's ball broke the offside trap once again and Kanoute slid the ball past Niemi into the back of the net.
It was not going to be Southampton's day as Peter Crouch wasted a golden chance to pull his side back into the game just before the break.
David Prutton's pass picked out Crouch inside the box, but with the goal at his mercy his close-range shot was superbly beaten out by Paul Robinson.
But Crouch made up for his error when he scored just two minutes into the second half. Ledley King failed to deal with Prutton's ball into the box.
The ball looped into the air and Crouch used his height to head the ball past the stranded Robinson.
But Defoe stole all the headlines when he grabbed his hat-trick on 60 minutes. Michael Brown's shot was only parried by Niemi and Defoe made no mistake string the rebound home.
Substitute Robbie Keane completed the rout on 87 minutes after Defoe's looping ball into the box was neatly put away by the Republic of Ireland international.
Man of the Match: Jermain Defoe – The England international capped a fantastic performance with a memorable hat-trick.