Now, in her latest film, Cake, she took on her riskiest and darkest role yet — playing a woman living with chronic pain, loss and addiction.
"For me it felt like I was going back to acting class," the 45-year-old admitted in an interview with CBC Radio's culture, arts and entertainment show Q.
Aniston strips down for her role in Cake as Claire Bennett — a woman struggling to cope under the shackles of chronic physical and emotional pain.
The star's physical transformation and raw, emotional performance earned her Golden Globes and Screen Actors Guild award nominations.
Aniston admits she couldn't have pulled it off during her decade playing coffee-serving Rachel on Friends, which ended its run in 2004.
"No way. Absolutely not. You have to have a level of life experience and wisdom to be able to access those parts of yourself ... in my 20s, I think I was doing just fine being Rachel."
Listen to Aniston's full interview with Q guest host Candy Palmater on CBC Radio one at 10 a.m.
The conversation will also be posted online after the broadcast, here.
Cake opens in theatres this weekend.