Hamilton, 62, is the head pastor of the largest United Methodist congregation in Kansas and a fifth-generation Kansan. He won the Democratic nomination in August and ran on affordability and on building a coalition across party lines. His slogan was "leading from the middle," and he promised to work with Republican Senator Jerry Moran. He also said he would not back Senator Chuck Schumer for majority leader if Democrats took control of the chamber. Roughly 12% of Republican and Republican-leaning voters supported him, and he drew independent and rural voters as Marshall's campaign struggled in the final weeks.

Marshall, 66, is a physician and an OB-GYN who has consistently backed Donald Trump's agenda. His campaign argued that the Senate majority was at stake, and he warned that "a vote for Adam Hamilton is a vote for Chuck Schumer and Democrat control of the Senate." Trump won Kansas by more than 16 points in 2024 and rallied for Marshall near Wichita on October 19, promising $8 billion in aid for farmers and year-round E15 fuel sales. Marshall nonetheless tried to distance himself from the president in the closing weeks, and national Republicans redirected millions of dollars to defend the seat. The Senate Leadership Fund, a Republican-aligned PAC, spent between $12 million and $14 million in the state. Ad-tracking figures put spending in support of Hamilton at $59.9 million, against $42.3 million in support of Marshall.

Both candidates took attacks. Reporting on Marshall's years as an OB-GYN said he sued more than 700 patients over unpaid bills, and that some had paychecks and bank accounts garnished. His campaign also left a bill of nearly $700 unpaid at a bakery for six years; Marshall paid $1,300 and said he was unaware of the debt. Opponents also pointed to his business ties to private equity executive Dan Tasset and to legislation benefiting physician-owned hospitals, and his campaign counsel said he "operates in full compliance with all applicable rules and laws." Hamilton faced ads alleging he covered up sexual assault scandals at his church.

In the final debate, Marshall proposed eliminating the cap on income subject to the Social Security payroll tax. Hamilton proposed raising the cap instead.

Voter surveys reported that most Marshall voters viewed him unfavorably, and that a majority of Hamilton's backers voted mainly to oppose Marshall. Mally Smith, a Democratic strategist, credited Hamilton with uniting Republicans, independents and Democrats, and pointed to a "blue environment" and a "scandal-plagued incumbent." Don Haider-Markel, a University of Kansas political science professor, said Hamilton's local popularity and political headwinds from Trump's policies also helped him. Voters were weighing the war with Iran, high diesel, gas and fertilizer prices in an agriculture-heavy state, healthcare costs and inflation. A YouGov poll taken from September 24 to October 4 found 53% of respondents disapproving of Trump's job performance and 46% approving.

Pre-election polling was mixed. The Cook Political Report rated the race a toss-up. One late-October poll had Hamilton ahead 49% to 45%, while a mid-October poll had Marshall ahead 48% to 47%.

Hamilton delivered his victory speech in a hotel ballroom in Overland Park, drawing on Bible passages and calling for decency in politics. Kansas was one of four Republican-held seats Democrats targeted in their effort to win a Senate majority, and Republican candidates also lost in deep-red states including Texas, Ohio and Iowa.