Fuller, who last started a match in November, arrived back only this week from a spell on loan at Ipswich.
Cardiff had no answer to his pace in the second half and only a Darren Purse tackle stopped him scoring a hat-trick.
There was no happy return to the south coast for Cardiff boss Dave Jones who was in charge of Saints until his controversial departure five years ago.
His team will now need an exceptional late run to stand any chance of forcing their way into the top six.
Southampton took the lead in the 47th minute from a rare goal by Claus Lundekvam - ironically the only survivor from the Jones era.
It was his first goal at home in 10 years of trying and only his second for the club.
Cardiff levelled on 54 minutes when Cameron Jerome forced the ball over the line for his 17th of the season after a goalmouth scramble in which the ball had twice been cleared.
Southampton regained the lead on 70 minutes when Fuller cut in from the right and beat Neil Alexander on his near post with a left-foot shot.
Fuller's second came five minutes later with a fierce left-foot shot from a Jermaine Wright corner on the left.
Cardiff didn't give up and in stoppage time Purse headed home a corner by Neal Ardley but Southampton held out for only their ninth win of the season.
Cardiff had a chance to level even further into injury-time with a 25-yard free-kick but Jason Koumas smashed his effort straight at Kevin Miller who held at the second attempt.