After being presented with the trophy, the brunette star teared up as she thanked her family, husband and fans.
She told reporters that her recent success was "unplanned, unexpected and unreal," adding: "I've had two wonderful experiences this year, and I think most actresses will tell you if you had one in five years, you'd be lucky."
This year looks to become a stellar one for Sandra, whose role in sports drama Blind Side has netted her the aforementioned nods, and has been generating Oscar buzz.
The movie has also made her the first female Hollywood star to carry a film across the $200 million mark at the US box office.
The feel good flick has so far grossed $208.5 million stateside since it opened in late November.
Other big winners included the Twilight team, who won favourite movie, top on-screen team, favourite franchise and the prize for best breakthrough actor went to newly-single Taylor Lautner.
There was also good news for Taylor's former girlfriend Taylor Swift, who was thrilled to be named favourite artist.
And Johnny Depp picked up favourite movie actor at the awards, which are voted for by US fans.
"The only reason any of us is up here is because of you," the Pirates of the Caribbean star told the crowd.
"It has been quite an amazing decade and an incredible ride, and I sincerely thank all of you for bestowing on me all your great treasures."