As TVLine reported, Mullally — who plays Karen in the series — missed two out of the 18 episodes.
Her mysterious exit came after she and Messing, 51, stopped following each other on Instagram this August.
Around that time, Mullally, 60, posted a cryptic Instagram Story saying, "One of the best feelings is finally losing your attachment to somebody who isn't good for you!”
In a separate post, she shared a quote which reads, "Don't ask people for directions if they've never been where you're going!"
Messing, meanwhile, took her own dig at Mullally by sharing a post supporting Emmy nods for the hit show and tagging all the cast members except Mullally.
RadarOnline.com previously reported that while the actresses tolerated each other when ratings were good, their relationship began to tank when the NBC show’s numbers did.
“Debra and Megan have never been close but now it is all-out war,” a source told Straight Shuter.
The insider added that shockingly, Mullally and Messing are fine not being friends, as they still act professional while filming, It’s Eric McCormack, however, who feels uncomfortable with their feud and is constantly trying to keep the peace.
“People worried… entirely too much” about Instagram-gate, he told Us Weekly earlier this year. “The four of us get along like a house on fire, we always have.”