The star opened up at The Hollywood Reporter's annual actress roundtable, where she was joined by Julianne Moore, Patricia Arquette, Amy Adams, Laura Dern, Hilary Swank and Felicity Jones.
When the question was broached about the recent treatment of Renee Zellweger, who garnered much unwanted attention over her appearance last month, Witherspoon responded:
"It's horrible. It's cruel and rude and disrespectful, and I can go on and on and on. It bothers me immensely.
"I know this is so Pollyanna of me, but why - and it's particularly women - why do they have to tear women down? And why do we have to tear other women down to build another woman up? It drives me crazy.
"Like, this one looks great without her makeup but that one doesn't look good without her makeup, and it's all just a judgment and assault that I don't - look, men are prey to it as well. I just don't think it's with the same sort of ferocity."
The star also revealed that even Oscar winners don't get every part, saying that she was "open to doing" Gone Girl (which stars Rosamund Pike), but director David Fincher didn't feel she was a right fit for the character.
Not that Reese has a lack of plum roles to choose from; she stepped out Wednesday for the premiere of her new film, Wild, in LA, which tells the story of Cheryl Strayed's 1000-mile-plus hike on the Pacific Crest Trail.