The Shrimpers reached the League Cup quarter-finals before being knocked out by Spurs in extra time at White Hart Lane on that occasion and they were out for revenge.
But the Londoners were far superior on this occasion, with Aaron Lennon providing the inspiration as goals from Robbie Keane, Jermaine Jenas and Mido rendered Freddy Eastwood's penalty strike meaningless.
Jenas was making his return after two months out with a groin injury, but looked fully fit again when running at the visiting defence on 11 minutes.
He played in Keane for what was about to be an easy tap-in, but Steven Hammell got back for a last-ditch tackle. However, the full-back's luck was about to drastically change a minute later.
Didier Zokora broke away from the back after a good tackle from Spurs debutant Ricardo Rocha on the edge of his own box.
The Ivory Coast international played in Keane, who lashed a shot against Hammell, who deflected the ball past his own keeper.
It knocked the stuffing out of the Shrimpers after a confident start, although they did have the chance to hit back on 16 minutes.
Eastwood chipped a delightful ball to the back post, but Mark Gower failed to make a strong enough connection to beat keeper Radek Cerny, making only his third start of the season.
It was a rare chance for the visitors as Spurs looked to kill of the tie before half-time. Keane hit the side-netting from a tight angle on 31 minutes and Rocha flashed a header across goal just moments later.
But midfielder Hossam Ghaly was causing most of the problems for Southend down the right-hand side.
The Egyptian worried Hammell on 39 minutes, beating him and pulling back a low cross for Keane, who forced a spectacular tip onto the bar from Darryl Flahavan.
Spurs even had strong appeals for a penalty turned down five minutes before the break, when Jenas appeared to be brought down by Adam Barrett.
But it seemed only a matter of time before the Premiership side extended their lead, and they had to wait only four minutes into the second half before doing so.
Lennon had been quiet up until then in an unfamiliar left-side role, but he suddenly came to life, turning Jamal Campbell-Ryce inside out before swinging a teasing cross to the back post, where the impressive Jenas was on-hand to tap home.
But again, Southend were rewarded with an opening straight after the re-start, with captain Kevin Maher forcing a fine save out of Cerny after an Alan McCormack cross fell to him on the edge of the box.
However, Martin Jol's side were in ruthless mood and they continued to press with Jenas seeing another effort well tipped over by Flahavan.
And after this amount of pressure, Jol will be distraught that Spurs allowed their lowly opponents back into the game with 20 minutes still to go.
A sloppy handball from Ghaly in his own box resulted in a penalty, which the quiet Freddy Eastwood slotted comfortably home.
Keane looked like the man most determined to restore Spurs' two-goal cushion, and he went on a solo run a minute later before putting the ball over the bar.
However, the Irishman was convinced he was fouled by Lewis Hunt just as he shot and his angry protests to referee Rob Styles earned him a booking.
It was left to the masterful Lennon to put the game beyond doubt, weaving past Hammell on the right to put in a low cross which Mido tapped in off the bar.