The freshman conservative has kept a low-profile for much of his first year in the Senate, but he has increasingly become a vocal critic of Trump, lashing him for his calls to ban Muslims and even questioning his extramarital affair from the 1990s.
In a surprising move, Sasse decided to stump in Iowa this week with Texas Sen. Ted Cruz, Carly Fiorina and Florida Sen. Marco Rubio to help bring down Trump.
The essence of Sasse's concerns boil to down to this: Trump is unvetted, lacks core convictions and has a sweeping view of the powers of the executive branch, calling him an "Obama Republican."
And he was not afraid to ridicule Trump for skipping the GOP debate Thursday night.
"He says he's a strongman but he's afraid of Megyn Kelly," Sasse told CNN.
He also took a personal swipe at Trump, blasting him over boasting about extramarital affairs, saying those affairs call into question Trump's character and trustworthiness.
"Isn't that weird that he brags about getting wives to break their oaths?" Sasse said. "I care if the guy takes an oath to the Constitution and keeps it."
Trump bragged about his sex life in his book "The Art of the Comeback," writing: "If I told the real stories of my experiences with women, often seemingly very happily married and important women, this book would be a guaranteed best-seller."
Sasse's campaign highlights how high the stakes are for conservatives ahead of next week's Iowa caucus. There is growing fear among Trump critics that he can roll to the GOP nomination if he wins on Monday, dramatically rewriting the conservative movement and putting his imprint on the future of the Republican Party.
"This guy is a salesman," Sasse said, hitting Trump over his past support for universal health care and gun control. "He's refreshing, but what's the core of his beliefs?"
Sasse also pleaded with the media to do a better job vetting Trump, cautioning that he could easily become president.
"I think people totally underestimate how persuasive he might be in a general election campaign," Sasse said. "So I think that Trump could well be the next president of the United States, but we already have a media that frankly, with all due respect, didn't vet President Obama. We didn't know what President Obama believed about executive restraint and about the constitution before he was elected. We don't need to have another guy run for office who hasn't been vetted."
The move to take on Trump is risky for the 43-year-old Sasse, who came to office on the strength of tea party conservatives who rallied behind his insurgent primary candidacy in 2014.
A Harvard graduate and former president of Midland University in Fremont, Nebraska, Sasse has been embraced by his party leadership for his serious approach to policy matters like health care, and has avoided the bomb-throwing ways in the mold of Cruz.
Yet Sasse has been getting attention in recent weeks with provocative statements, starting in November when he delivered his first Senate floor speech, sharply repudiating both parties and questioning the effectiveness of the institution.
"If I can be brutally honest for a moment: I'm home basically every weekend, and what I hear and what I'm sure most of you hear is some version of this: A pox on both parties and all your houses," Sasse said. "We don't believe politicians are even trying to fix this mess. To the Republicans, to those who claim this new majority is leading the way: Few believe that."
Sasse declined to say if he would back Senate Majority Leader Mitch McConnell as the GOP leader next Congress, saying he wouldn't speculate on future leadership races, while reiterating his message that Washington is broken.
"And there's not a lot of forward thinking in Washington. I believe the people of this country are more urgent about the big problems the country faces than the people who are paid to be their leaders," Sasse told CNN.