He has taught at the University of Texas and served as an assistant secretary in the U.S. Department of Health and Human Services in the George W. Bush administration.

On February 13, 2021, Sasse was one of seven Republican senators to vote to convict Donald Trump of incitement of insurrection in his second impeachment trial.

[6] After his resignation, it was revealed that Sasse had spent an unusual amount of money as president of the University, much of which went to lucrative consulting contracts and high-paid, remote positions for his former staffers and GOP allies.

[12][13] Sasse's doctoral dissertation, "The Anti-Madalyn Majority: Secular Left, Religious Right, and the Rise of Reagan's America", won the Theron Rockwell Field[14] and George Washington Egleston[15] Prizes.

Sasse left the Department of Justice to serve as chief of staff to Representative Jeff Fortenberry from January to July 2005.

[18] In July 2007, President George W. Bush nominated Sasse to the post of assistant secretary for planning and evaluation in the U.S. Department of Health and Human Services.

[22][23] In October 2009, he officially joined the Lyndon B. Johnson School of Public Affairs Center for Politics and Governance as a fellow, before being appointed president of Midland University.

[27][32] When nearby Dana College was forced to close, Sasse hired much of its faculty and enabled most of its students to transfer to Midland.

[35] In October 2013, Sasse announced his candidacy for the Senate seat held by Republican Mike Johanns, who was not seeking reelection.

[40] Sasse's response was that in his articles and speeches, he was describing the political landscape rather than giving his own opinions on the ACA's merits; to a World-Herald reporter, he said, "I have never changed my position on thinking Obamacare is a bad idea".

[45] In February 2019, Sasse was one of 16 senators to vote against legislation preventing a partial government shutdown and containing $1.375 billion for barriers along the U.S.–Mexico border that included 55 miles of fencing.

[46] In March 2019, Sasse was one of 12 senators to cosponsor a resolution that would impose a constitutional amendment limiting the Supreme Court to nine justices.

The resolution was introduced after multiple Democratic presidential candidates expressed openness to increasing the number of seats on the Supreme Court.

Sasse was participating in the January 6, 2021, certification of the 2021 United States Electoral College vote count when Donald Trump supporters stormed the U.S. Capitol.

[49] Sasse added that he would consider articles of impeachment if presented with them in the Senate, contending that Trump had "disregarded his oath of office".

[60] His appointment generated some controversy on campus, with Sasse's past comments on same-sex marriage leading to student protests.

[61] The Faculty Senate also passed a no-confidence resolution expressing concern for the lack of transparency surrounding Sasse's selection.

The new hires included former Senate staffers and other Republican officials, many of whom worked outside of Florida, resulting in increased travel costs.

[63] An audit conducted by the Florida Auditor General found Sasse inappropriately spent university funds, including by paying above-market-rate salaries to his former congressional staffers who were not competitively hired and by chartering private jet flights without clear business purposes.

[68][69] Huawei's CFO Meng Wanzhou, daughter of the company's founder Ren Zhengfei, was arrested in Canada on December 1, 2018, at the request of U.S. authorities.

Sasse said that China is undermining U.S. national security interests, often "using private sector entities", and "Americans are grateful that our Canadian partners have arrested the chief financial officer.

[74][75] Sasse voted against the bipartisan criminal justice reform legislation, FIRST STEP Act, which passed with near-unanimous consent.

[84] In January 2019, Sasse was one of 11 Republican senators to vote to advance legislation intended to block Trump's intent to lift sanctions against three Russian companies.

[88] Sasse voted to acquit Trump in his first impeachment trial in the Senate over his request of Ukrainian president Volodymyr Zelenskyy that he start an investigation into political rival Joe Biden.

[93] In an October 2020 campaign town hall event, Sasse remained critical of Trump: "He mocks evangelicals behind closed doors.

[97] He was the first Republican to criticize Senator Josh Hawley's plan to challenge the results during Congress's count of the electoral votes on January 6, 2021, saying such an action would "disenfranchise millions of Americans" and that it would "point a loaded gun at the heart of legitimate self-government".

[52] On May 27, 2021, along with five other Republicans and all present Democrats, he voted to establish a bipartisan commission to investigate the January 6 United States Capitol attack.

[108] In announcing his Senate candidacy, Sasse expressed strong opposition to the Affordable Care Act (ACA), calling himself "the anti-Obamacare candidate"[109] and declaring that "If it lives, America as we know it will die.

The Supreme Court once again overstepped its Constitutional role by acting as a super-legislature and imposing its own definition of marriage on the American people rather than allowing voters to decide in the states.

[125] He later became an elder in the United Reformed Churches in North America and served on the board of trustees for Westminster Seminary California.