League leaders Manchester City are the only side to have beaten Sean Dyche's men away from Turf Moor in this campaign, with the Clarets turning around last term's dismal record on the road - where they won just once - in spectacular fashion.
This victory may be somewhat less heralded - and less surprising - than the opening day defeat of champions Chelsea, but it had not looked like coming until Vokes was introduced as a second-half substitute.
Nick Pope - a Premier League player of the month nominee - was equal to everything Mauricio Pellegrino's men mustered going forward, with an assured defensive display from Sean Dyche's Burnley looking to have sealed a hard-fought draw.
But with the visitors' first effort on target, Vokes directed a header beyond the flailing Fraser Forster to earn the points.
Manager Dyche continues to be linked with the vacant Everton post, but it was Merseyside rivals Liverpool he had in his sights here as - at least until the Reds face West Ham later in the day - Burnley moved above them up to sixth.
What a header from Sam Vokes as he meets Gudmundsson's cross and buries a magnificent header past Forster from 12 yards. What a goal! 1-0— Burnley FC (@BurnleyOfficial) November 4, 2017
The hosts dominated possession early on, but their measured approach play too often concluded with a direct ball that suited a sturdy Burnley backline.
When finally, after 26 minutes, the Saints full-backs combined and Cedric Soares picked out Ryan Bertrand in the area, the looping header from the latter dropped harmlessly off target.
Pope was belatedly forced into a first save just over 10 minutes before half-time, beating away Sofiane Boufal's strike after he met a loose ball at the back post.
Southampton stepped up a gear after that opening and Pope was at full stretch again to keep out Nathan Redmond's low drive.
Another smart Pope stop kept out Maya Yoshida's dipping left-footed volley following the restart, but the home side's momentum waned.
Dyche introduced Ashley Barnes and Vokes from the bench in the hope of stealing a winner at the other end and the changes had an impact, at least pushing Burnley further up the pitch.
And Vokes took his opportunity when it arrived on 81 minutes, nodding in a Johann Berg Gudmundsson cross in a stunning smash-and-grab.
Key Opta stats:
- Southampton have failed to score in nine of their last 12 Premier League home games (W2 D4 L6).
- In contrast, Burnley have kept clean sheets in five of their last eight top-flight matches, including each of the last two.
- Burnley have picked 19 points after their first 11 games this season – their best record at this stage of a top-flight campaign since 1973-73 (24 points - assuming three points for a win).
- The Clarets had picked up just one point after their first six away Premier League games last season, they’ve already picked up 11 this season – more than they collected in the whole of last season on the road (7).