The stars, who play Grace Adler and Karen Walker on the hit sitcom, have sparked speculation that a falling out was the reason behind the shock cancellation of the show.
Mullally, 60, also posted a cryptic message in a since-deleted Instagram post, hinting at the issues between the pair.
“One of the best feelings is finally losing your attachment to somebody who isn’t good for you!” she wrote.
Mullally also posted, “Don’t ask people for directions if they’ve never been where you’re going!”
Messing meanwhile uploaded a post calling for fans to vote for Will & Grace for the Emmys but failed to tag Mullally.
Their co-stars Eric McCormack and Sean Hayes still follow both women and they follow them back.
It follows the surprising news that the rebooted Will & Grace would not be returning for another season despite decent ratings.
Messing was cast as interior designer Grace Adler when they show began in 2006.
She lived with her gay best friend, Will Truman, with Mullally playing her alcoholic assistant, Karen Walker.
The show ran for eight seasons before being rebooted in 2017.
Fans were left devastated that Messing and Mullally may longer be friends.
what do you think about the whole debra messing/megan mullally situation??? — I’m honestly really sad about it. I love them a whole lot and it’s kinda breaking my heart a lil bit https://t.co/ZqB21FDiAY— 𝖊 𝖑 𝖑 𝖎 𝖊 (@bisexualwalker) August 14, 2019
debra messing and megan mullally are no longer friends my life is falling apart— ♡ F a y (@talesforfaith) August 13, 2019
Megan Mullally and Debra Messing unfollowing each other... I finally know what it feels like to be a child of divorce— Jess (@catsploitation) August 13, 2019
okay so do we know what happened with debra messing and megan mullally or no??— joyce 🇬🇷♡ (@babyyaniston) August 13, 2019
so people are saying that megan mullally and debra messing aren't friends anymore and ive never been sadder in my whole life— sandra oh enthusiast (@oceansyang) August 12, 2019
awake and lying in bed wondering what happened between megan mullally and debra messing to force them both to unfollow each other on insta ??? cos what else would i be doing— K♡ (@_IamKayleigh) August 12, 2019
I watch the Golden Globes pre-show last night and Debra Messing said that she was there alone that nobody else from the show was there because only she was nominated. Later, watching the show, Megan Mullally presents an award. Anybody else find this concerning or odd????????????— Erasmus Bramble (@alfiefairbairn) January 7, 2019