With a new Formula One record of eight successive victories in one season in his sights, the four-times world champion appears poised to complete the feat in Sunday's United States Grand Prix.
For a brief moment, with one minute of the final hour-long practice session remaining at the Circuit of the Americas, a surprise was in store as Sauber's Nico Hulkenberg topped the timesheets.
At that stage the German was seven thousandths of a second quicker than Vettel, but the latter was far from done as he then blitzed the track to go half-a-second faster than Hulkenberg.
Come the conclusion to the session and with a lap of one minute 36.733 seconds, Vettel finished 0.203secs ahead of Red Bull team-mate Mark Webber.
Mercedes' Lewis Hamilton proved to be the closest challenger to the Red Bull duo, finishing 0.331secs adrift, with Hulkenberg fourth.
Lotus' Romain Grosjean was fifth, 0.612secs down, with new team-mate Heikki Kovalainen a disappointing 13th and half a second adrift of the Frenchman.
Standing in for Kimi Raikkonen, who underwent successful back surgery on Thursday, the hastily signed-up Kovalainen managed to finish ahead of Grosjean following Friday's two 90-minute sessions.
On this occasion, however, Kovalainen may struggle to break into the top 10 in qualifying, which will be his first since being axed a year ago by Caterham.
McLaren's Jenson Button was a positive sixth, although he will need to follow up with an equally strong outing in qualifying to negate the three-place grid penalty he received on Friday for overtaking under red flag conditions.
Mercedes' Nico Rosberg and Sergio Perez in his McLaren were seventh and eighth fastest, and the only other drivers to finish within a second of Vettel.
Williams' Valtteri Bottas and Adrian Sutil in his Force India rounded out the top 10, with the latter 1.015secs back.
As for Ferrari, desperately battling Mercedes for second place in the constructors' standings, Fernando Alonso and Felipe Massa were 11th and 17th respectively, the latter 1.6secs adrift.
Paul Di Resta could only managed 16th, half a second behind team-mate Sutil, with Marussia's Max Chilton propping up the standings with a time 4.5secs off of Vettel.