MacDonough began her career in 1990 as a legislative reference assistant in the Senate library and later as assistant morning business editor to the Congressional Record. She left in 1995 to attend Vermont Law School, graduating with a JD in 1998. During law school, MacDonough interned with Judge Royce C. Lamberth and the Immigration and Naturalization Service in Burlington, Vermont. After graduating, she worked as a trial attorney for the United States Department of Justice handling immigration cases in New Jersey. MacDonough joined the office of the Senate Parliamentarian in May 1999 as an assistant parliamentarian and was promoted to senior assistant parliamentarian in 2002. She advised then-Vice President Albert Gore on the procedure for counting ballots following Bush v. Gore. At her appointment to Parliamentarian in 2012, she was praised by outgoing Parliamentarian Alan Frumin as "down-to-earth," describing her personal knowledge of Capitol staffers; and by Senator Richard Shelby as "smart, diligent... and she's got integrity." Sen. John Thune said "she's very steeped in the traditions of the Senate and understand how it works here" and Sen. Mark Warner said he had "no question about her ability to read the rules and make the right decisions." During the 2015 congressional effort to partially repeal the Patient Protection and Affordable Care Act, MacDonough ruled the provision that would roll back the Independent Payment Advisory Board disqualified the 2015 package from consideration as a reconciliation bill in the Senate under the Byrd Rule, which requires that reconciliation bills must have a budgetary effect. Rather than the simple, filibuster-free 51-vote majority required to pass a reconciliation bill, the 2015 package would require a 60-vote threshold to pass in the Senate, which effectively killed the legislation in the Senate, as Republicans did not hold the requisite votes. Sen. Ted Cruz commented MacDonough should be fired or ignored, although since the procedural rulings are officially made by the president of the Senate, firing MacDonough would have made no difference, and Sen. John Cornyn, the senior senator from Texas, dismissed Cruz's comments, saying ousting MacDonough would be "like firing the judge if you disagree with his ruling." During the passage of the Tax Cuts and Jobs Act of 2017 MacDonough ruled the repeal of the Johnson Amendment, which limits the political speech of churches, could not be included in the bill. In January, 2017, Rep. Paul Ryan said that MacDonough would be the person to "watch" in the Senate, because budget reconciliation would likely again be the tool used to pass amendments to the Affordable Care Act. In 2017, MacDonough read the language of Senate Rule XIX to freshman Senator Steve Daines, which Daines carefully repeated while warning Sen. Elizabeth Warren for reading statements from Ted Kennedy and Coretta Scott King condemning the nomination of Jeff Sessions. The Senate subsequently voted 49 to 43 to uphold Majority LeaderMitch McConnell'sobjection that Warren had impugned Sessions's character. In a 2018 commencement speech at her alma mater, Vermont Law School, MacDonough called the invocation of the 'nuclear option' in 2013 and 2017 as a "stinging defeat that I tried not to take personally". The 2013 vote removed the need for a three-fifths supermajority for cloture for all executive and judicial nominations bar those for the Supreme Court, while the 2017 vote removed the requirement for nominations to the Supreme Court. MacDonough received attention prior to the 2020 impeachment trial of Donald Trump due to her role in advising Chief Justice John Roberts on parliamentary procedure while presiding over the trial. MacDonough has been praised by former President pro temporePatrick Leahy and former majority whip John Cornyn, with Leahy saying that he had "been here with many, many parliamentarians. All were good. But she’s the best." and Cornyn saying that "she's tough" and "she calls them straight down the middle." In June 2020, MacDonough provided a decision to Senator Josh Hawley ruling that a vote on the Senator's WTO withdrawal resolution was in order. However, she had to reverse herself two weeks later after pressure from Senator Chuck Grassley and Senator Ron Wyden. MacDonough speaks publicly only once a year, to address the United States Senate Youth Program.
