The spat began when Stelter shared a piece about the significance of disinformation that has plagued social media.
"We have this alternative media ecosystem that is driving a lot of disinformation. It is not understood by journalists or anyone really beyond a very small group of people who are really engaged with it," Stelter tweeted, quoting Bellingcat executive director Eliot Higgins.
O'Brien, a former CNN anchor, took exception to Stelter's tweet.
"Also mainstream media outlets frequently book guests who lie, intentionally, on their air. CNN is one such outlet," O'Brien told Stelter. "Instead of shunning those guests they are booked again and again and again."
She then took direct aim at the media guru.
"When CNN’s media reporter pretends his own news org isn’t part of this BS, it’s a problem," O'Brien said.
This isn't the first time O'Brien went after Stelter. Last month, she ripped the CNN icon for his response when asked how networks can get Americans interested in the impeachment hearings.
“I also think, episode one so to speak, matters a lot, and I hate to say that because we’re talking about basic democracy at risk here. But from a television perspective, Democrats have to come out strong in that first episode,” Stelter said during a CNN segment. “For the same reason when we’re watching Netflix or listening to a new podcast, we only choose to keep listening if we’re interested in episode one.”
“Why is CNN so stupid about important s--t? This is Cillizza-level inanity. Brian should be ashamed of himself,” O’Brien reacted, referring the often-mocked CNN political analyst Chris Cillizza in the process.
Fox News' Brian Flood contributed to this report.