Boufal, who joined the Saints for a club record fee of £16m from Lille in August, collected the ball from James Ward-Prowse before blasting past Boro goalkeeper Victor Valdes.
Viktor Fischer had the visitors' best chance but his shot was blocked on the goalline by Jose Fonte.
The result takes Southampton up to 10th in the table, while Middlesbrough are 16th, only three points above the relegation zone.
The Saints were playing their 24th game of the season, and their third of seven in December with a minimum of seven more matches to come in January.
Puel made eight changes from the side that drew 1-1 against Hapoel Be'er Sheva in the Europa League on Thursday, a result that meant they were eliminated from the competition.
Midfielder Sam McQueen and forward Jay Rodriguez were both making their second Premier League starts of the season, while Boufal and Cuco Martina had only previously started five league games between them in 2016-17.
But the gambles paid off with the Saints returning to the top half with a well deserved victory.
Indeed, the winning margin could have been bigger, but Rodriguez had a header cleared off the line and shot over the bar from close range late on.
For Middlesbrough, their problems in front of goal continue and their tally of 13 goals from 15 games is the worst in the division.
With joint top scorer Alvaro Negredo and Gaston Ramirez, who scored the only goal in their 1-0 win over Hull on Monday, both injured, Jordan Rhodes started a Premier League match for only the second time.
However, Rhodes only created one chance, a low shot from a tight angle which home goalkeeper Fraser Forster comfortably saved with his legs.
That effort was one of only two shots on target for the visitors in the whole match, with none coming in the second half.
Boro's only other opportunity came when Fischer, still without a Boro goal in 11 appearances since joining from Ajax in the summer, went round Forster but his shot was blocked by Fonte.
Middlesbrough boss Aitor Karanka's hopes of keeping his club in the Premier League and avoiding an instant return to the Championship could depend on whether he can bolster his attacking options in January.
Man of the match - Sofiane Boufal (Southampton)
Viktor Fischer had the visitors' best chance but his shot was blocked on the goalline by Jose Fonte.
The result takes Southampton up to 10th in the table, while Middlesbrough are 16th, only three points above the relegation zone.
Puel's rotation pays off
How Southampton rotate their squad in a hectic period is going to be one of the biggest challenges Claude Puel has faced so far during his spell in charge.The Saints were playing their 24th game of the season, and their third of seven in December with a minimum of seven more matches to come in January.
Puel made eight changes from the side that drew 1-1 against Hapoel Be'er Sheva in the Europa League on Thursday, a result that meant they were eliminated from the competition.
Midfielder Sam McQueen and forward Jay Rodriguez were both making their second Premier League starts of the season, while Boufal and Cuco Martina had only previously started five league games between them in 2016-17.
But the gambles paid off with the Saints returning to the top half with a well deserved victory.
Indeed, the winning margin could have been bigger, but Rodriguez had a header cleared off the line and shot over the bar from close range late on.
For Middlesbrough, their problems in front of goal continue and their tally of 13 goals from 15 games is the worst in the division.
With joint top scorer Alvaro Negredo and Gaston Ramirez, who scored the only goal in their 1-0 win over Hull on Monday, both injured, Jordan Rhodes started a Premier League match for only the second time.
However, Rhodes only created one chance, a low shot from a tight angle which home goalkeeper Fraser Forster comfortably saved with his legs.
That effort was one of only two shots on target for the visitors in the whole match, with none coming in the second half.
Boro's only other opportunity came when Fischer, still without a Boro goal in 11 appearances since joining from Ajax in the summer, went round Forster but his shot was blocked by Fonte.
Middlesbrough boss Aitor Karanka's hopes of keeping his club in the Premier League and avoiding an instant return to the Championship could depend on whether he can bolster his attacking options in January.
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