Maher fought with rapper Killer Mike - real name Michael Render - and Washington Post reporter Robert Costa as they joined him as panelists on his appearance Friday night.
The host denounced the "outrageous" incident last weekend when Senator Sinema was stalked into a bathroom and bothered by progressive activists at Arizona State University.
The demonstrators, with social justice group Living United for Change in Arizona, were seeking to confront the Democratic senator for Arizona over her opposition to Joe Biden's $3.5 trillion budget reconciliation plan.
Simena and fellow moderate Democrat Senator Joe Manchin are refusing to support the spending bill while progressives are declining to support the bipartisan $1 trillion infrastructure plan unless they do - producing a stalemate.
This has forced Democrats to go back to the drawing board on the $3.5 trillion agenda as they try to whittle it down to just $2 trillion.
Maher blasted the activists during his monologue where he branded them a "gang" and said it was "over the top."
"It's getting chippy out there. She was at ASU and a gang of Gen. Z activists followed her into the bathroom," he said.
"Then they went back to demanding that we make campuses a safe space," he ridiculed.
Maher continued: "I think that's a little over the top."
The TV host tried to slam the incident as he discussed the current battle between the moderates and progressives within the Democratic party with his guest panelists.
"I think this is outrageous," Maher said of the harassment of Simena, reported Fox News.
"You may not like the politics, but when this s**it starts to happen, I don't know where the safe space is in America. And I don't know where it ends."
Render admitted that he "doesn't think it's right" to follow a lawmaker into a bathroom but said Democrats "need to bring something home" with the spending bills as he suggested that people are getting "angry".
Maher rebuked his comments, claiming that progressives are asking for too much.
"But one reason they're not bringing anything home - they could have that $1 trillion infrastructure bill," he said.
"And, by the way, $1 trillion – still to some people, is a lot of money."
"It's a lot of jobs, building bridges and roads and all kinds of stuff. That's being held up, Mike, by people who are saying what you're saying: 'We want everything and we want it now. And if we don't get it, then you don't get anything.'"
On Friday, it was reported that Sinema reportedly wants to delete $100 billion in climate proposals from the spending bill making its way through Congress.