The 34-year-old has signed a one-year deal with the Championship side, having been released by Stoke last month.
Upson spent the final five months of last season on loan at Albion, making 20 appearances and contributing to a miserly defence that conceded just 15 goals during his time at the Amex Stadium.
David Burke, Brighton's head of football operations, said: "We are delighted that Matt has agreed to come back to the club. His experience is fantastic and it really shows our intent by bringing in someone of Matt's pedigree.
"It's not like he's a new signing because he's been with us for almost six months and he knows exactly what we are all about.
"He brings continuity and stability to the defence, which is what we were looking for, and it bodes well for us to keep the strong defence that we had last season."
He added: "His experience will bring more impact to the players as he spends more time with them, particularly during pre-season, which is a key time for tactics and strategies to be embedded into the players. Matt has experienced that at the highest level.
"We finished with the best defensive record in the league and we will build on that for the coming season."
Upson joined up with the Brighton squad on Wednesday morning and will travel to Madrid for a pre-season training camp on Sunday.