Ever since then, the Los Angeles neighbours' friendship has flourished beneath the media spotlight. So much so, that the Hollywood power players are set to star in forthcoming Amazon television series The Morning Show.
In celebration of their long-awaited small screen reunion, we chart their sweetest moments from red carpet pranks to that matchy-matchy fashion moment.
The countless times Reese has gushed over Jennifer
Back in 2011, Witherspoon gushed over the award-winning actress describing her as the "incredible combination of sex appeal and complete lovability".
"You just want to get your nails done with her and you want to make out with her - at least I do," she joked. "And that's what we do sometimes on Saturdays. First we get our nails done and then we make out. It's totally awesome."
If that wasn't enough for us to agree with (and leave Aniston blush-faced), she continued to flaunt their love affair the following year.
"I have a major girl crush on Jennifer Aniston but doesn't everybody have a crush on Jennifer Aniston?" Witherspoon said in 2012. "Like, dogs have crushes on Jennifer Aniston. Those dogs are like, 'I wish it was me in Marley and Me.' She's so cute!"
When Jennifer lovingly referred to Reese as family
Proving their relationship transcends beyond the small screen, Aniston referred to the actress as family at the 2015 Academy Awards.
"Look at [Reese], she's so cute," she enthused. "So pretty, she's my little sister, even if she's [just] my TV sister."
That time Reese pinched Jennifer's rear on the Oscars red carpet
During the same interview, Witherspoon played a cheeky prank on her friend.
Whilst Aniston was busy answering interview questions on the red carpet, the actress creeped up behind her and pinched the Hollywood heavyweight's rear.
"Oh! Hi, honey," Aniston responded, blowing her a kiss. "Look at her, she's so cute!"
When Jennifer had a major fangirl moment on stage
Later that year, Aniston sang the actress' praises once more.
Taking to the stage to honour Witherspoon at the 29th American Cinematheque Awards, she described herself as a "fan, friend and for two fun-loving episodes - her loving TV sister".
"Even before Reese played my lovely, albeit somewhat spoiled, sister Jill, she somehow felt like family to me," the award-winning actress began. "Reese's amazing talent, both professionally and personally, has long made her a very strong and welcome presence in my life - and I'm sure in many people's lives in this room."
"Reese is not only an extraordinary actress, she also knows how to make a really excellent first impression," Aniston continued, recalling Witherspoon's acting breakthrough in 1991 flick The Man In The Moon.
We're not crying, you are.
It turns out, Jennifer is behind Reese's latest career move
When news of the friends' forthcoming Amazon project, The Morning Show, first graced the headlines back in 2017, Witherspoon revealed that Aniston was a driving influence behind her latest career venture.
"I'm excited because I get to work with Jen every day for a long time," she told Extra. "She was a big part of why I ended up doing it and we both were really part of getting the project going from the beginning."
When the duo recreated a famous Friends scene
It's been almost two decades since Friends left our television screens for good (we're not counting our weekly binge sessions of course) but the pair have still got it.
During a recent press interview, Aniston (Rachel Green) and Witherspoon (Jill Green) recreated a famous argument from the cult series which was later shared on Instagram.
Admittedly, it had been so long that Aniston forgot her lines but thankfully, Witherspoon was on hand to help her out.
When the A-list pals twinned on the red carpet
For the latest leg of the The Morning Show press tour, the duo further cemented their status as the world's best-dressed friends in matching ensembles.
Aniston posed for the New York photo call in a floor-sweeping James Galanos number while her onscreen-offscreen bestie graced the red carpet in a cold-shoulder Céline gown.
When Jennifer gave Reese a confidence boost on set
During a recent interview, Witherspoon revealed how Aniston helped to boost her confidence at the beginning of her career on the set of Friends.
"She was so sweet to me. I was really nervous, and she was like, 'Oh, my gosh - don’t worry about it!'," she recalled. "I marvelled at her ability to perform in front of a live audience like that with no nerves. They would change all the lines and she was just so effortlessly affable, bubbly, and sunny. We’ve been friends ever since."
Don't suppose there's room for one more friend?