The beautiful brunette – better known for her comedic roles – was again honoured for her portrayal of tough real-life mum Leigh Anne Tuohy in The Blind Side.
And in a room filled with her silver screen peers she paid a loving and humorous tribute to her husband, Jesse James.
"You get dressed up in monkey suits and you sit at a table with people you don't know," she said. "And I leave you there, and then you come back with, like, Morgan Freeman's email. I don’t know how you do it."
"I love you so much, and you're really hot. And I want you so much!" she added.
Other stars returning to the winner's podium included best actor Jeff Bridges who was hailed once more for his work in Crazy Heart, which tells the story of a down and out country singer.
Christopher Waltz was named best supporting actor for his role in Inglourious Basterds – the cast of which won best ensemble performance – while Dexter's Michael C Hall again accepted an award for best actor in a drama series.
Precious' Mo'Nique won best supporting actress at the LA ceremony, best comedy actor and actress were 30 Rock's Alec Baldwin and Tina Fey, and hit show Mad Men won best ensemble drama series.
Musical newcomer Glee took best ensemble cast comedy series, Julianna Marguiles was named best actress in a drama series for The Good Wife and best actor and actress in a TV movie were Taking Chances' Kevin Bacon and Grey Gardens' Drew Barrymore.
Golden Girl Betty White was this year's winner of the lifetime achievement award.
Sandra and Jeff's success at both prestigious awards' events this month have certainly boosted their chances at the Academy Awards in March.
But that's not something the 45-year-old actress wants to focus on for the moment.
"Shhhh. Shhhh. Shhhh," Sandra said backstage when ask to speculate on her Oscar chances.
"I would be a hostess or a waitress or a house restorer before I ever consider myself an actor, because I never thought I was good enough."