But it’s her on-screen and off-screen friendship with co-star Chelsea Handler that has everyone raising eyebrows.
Even the typically sweet actress is confused about how she became so close to the potty-mouthed late night comedian.
“We’re the most unlikely friends – like on ‘Animal Planet’ where the giraffe and turtle make friends,” Witherspoon told Fox411's Pop tarts column regarding her Handler friendship. “That’s us.”
The Oscar-winning actress, who last year tied the knot for the second time with Hollywood agent Jim Toth, also said she knows precisely what characteristics a man requires to keep her happy.
“Great character, loyal and honest,” she declared.
And if Witherspoon, who won her Oscar for her moving portrayal of country music legend June Carter, was ever to stand before Jennifer Lopez on “American Idol” – she already knows what tune she would belt.
“’Angel from Montgomery,’ the John Prine song,” she quipped.