Bullock and Aniston joined another of Handler's best pals, actress Mary MCCormack, to stage a mock intervention and hold the host exactly what they thought of her.
MCCormack blamed the funny lady for wrecking her acting career and landing her with a bad reputation, while Aniston criticised Handler for stealing "everything I do", adding, "I introduced you to my yoga teacher (and) you stole my yoga teacher," and, "You're not fooling anyone with those blue eyes... I mean seriously, who dyes their eyes? That's just weird."
The former Friends star then took aim at her pal's hygiene issues, explaining, "My security guard caught you douching with Listerine!"
Bullock, who told Handler "You still scare me a little", scolded her pal for teasing lesbians, adding, "You're either into girls or you're not".
The Gravity star then brought Handler's "ex-lover" 50 Cent onto the studio stage, insisting he was the last thing that was cool about the host.
The comedienne appeared thrilled to see her ex, who she admitted she hadn't seen since they split.
She told the rapper, "I wanted to apologise because I did end our relationship abruptly and I know you didn't come on the show for many years... but I want you to know that I have not dated a black man since.
"They say, 'Once you go black, you never go back...' You come running back!"
She then joked, "But seriously, are you over me?"
The rapper then performed new single Watch Me with his rap collective G-Unit before walking off stage hugging his ex, who could be heard saying, "Thanks, babe."
Handler wrapped up the hour-long special with a performance from Miley Cyrus, who sang Roy Orbison's It's Over, dressed in a western style shirt and red pants, before Gwen Stefani led an all-star choir with a send-off spoof of USA For Africa's We Are The World.
The celebrities who joined her, Handler, 50 Cent, Bullock, Aniston and MCCormack onstage included Vanessa Hudgens, Fergie, Trace Adkins, Avril Lavigne, Gerard Butler, Alanis Morissette, Kate Beckinsale, Justin Theroux, Selena Gomez, Melissa MCCarthy, Dave Grohl, Leann Rimes, Sammy Hagar, Chloe Grace Moretz, Johnny Knoxville, astronaut Buzz Aldrin and Anna Faris.