After the death of incumbent senator Thomas Walsh, Montana governor John Erickson resigned and was appointed by his successor as an interim to the seat.<ref name=knoxvillefocus/> Erickson faced outrage from constituents who suspected cronyism, and Murray was encouraged to run for the seat in the 1934 special election. In an upset, he won the primary in a field of six candidates with a plurality of 25%,<ref>[https://www.ourcampaigns.com/RaceDetail.html?RaceID=501302 MT US Senate - D Primary Race - Jul 17, 1934]. ''Our Campaigns''. Retrieved August 2, 2021.</ref> and easily defeated [[Republican]] opponent Scott Leavitt in the general election.<ref>[https://www.ourcampaigns.com/RaceDetail.html?RaceID=267909 MT US Senate - Special Election Race - Nov 06, 1934]. ''Our Campaigns''. Retrieved August 2, 2021.</ref> Two years later, Murray only barely defeated a primary challenger and proceeded to win re-election for a full Senate term.<ref name=knoxvillefocus/>
A strong supporter of [[Franklin D. Roosevelt]] and New Deal programs during the [[Great Depression]], Murray stayed loyal to the president even during the 1937 [[court packing]] attempt.<ref name=knoxvillefocus/> Unlike his Democrat colleague [[Burton K. Wheeler]] from the state's Class I seat, <ref name=archives/> he never significantly broke with Roosevelt, though ultimately did vote to recommit the Judicial Procedures Reform Bill for committee.<ref>[https://www.govtrack.us/congress/votes/75-1/s42 TO RECOMMIT TO THE COMMITTEE ON THE JUDICIAL BRANCH OF GOVERNMENT. S. 1392, A BILL TO REORGANIZE THE JUDICIARY BRANCH.]. ''GovTrack.us''. Retrieved August 2, 2021.</ref>
Murray voted in 1937 to table two [[anti-lynching law|anti-lynching]] rider amendments along with the majority of his party.<ref>[https://www.govtrack.us/congress/votes/75-1/s43 TO TABLE AN AMENDMENT TO S. 69, THE INTERSTATE COMMERCE ACT. THE AMEND. OFFERED BY SENATOR COPELAND WHICH WOULD HAVE ADDED HOUSE BILL 1507, THE ANTILYNCHING BILL, TO S. 69, A BILL LIMITING THE SIZE OF TRAINS IN INTERSTATE COMMERCE.]. ''GovTrack.us''. Retrieved August 2, 2021.</ref><ref>[https://www.govtrack.us/congress/votes/75-1/s58 TO TABLE AN AMENDMENT TO S. 2475. OFFERED BY SENATOR COPELAND WHICH WOULD HAVE ADDED THE ANTILYNCHING BILL AS PERFECTED BY THE SENATE COMMITTEE ON THE JUDICIARY TO THE PENDING LEGISLATION.]. ''GovTrack.us''. Retrieved August 2, 2021.</ref> In early 1947, he split votes on tabling two motions by [[Louisiana]] Democrat [[John H. Overton]],<ref>[https://www.govtrack.us/congress/votes/80-1947/s2 S RES 1. WHITE MOTION THAT THE OATH OF OFFICE BE ADMINIS- TERED TO BREWSTER. TAFT MOTION TO TABLE OVERTON MOTION TO SUBSTITUTE THE NAME OF BILBO.]. ''GovTrack.us''. Retrieved August 2, 2021.</ref><ref>[https://www.govtrack.us/congress/votes/80-1947/s1 S RES 1. RESOLUTION TO REFER TO RULES COMMITTEE BILBO'S CLAIM TO A SENATE SEAT. OVERTON AMEND. TO PERMIT OATH TO BE ADMINISTERED TO BILBO. TAFT MOTION TO TABLE BOTH RESOLUTION AND AMEND.]. ''GovTrack.us''. Retrieved August 2, 2021.</ref> which sought to prevent racist [[Mississippi]] demagogue from being kicked out of the Senate after the latter openly threatened blacks in his 1946 re-election campaign.<ref>Fleegler, Robert L. [http://www.mississippihistory.org/sites/default/files/bilbo.pdf Theodore G. Bilbo and the Decline ofPublic Racism, 1938-1947]. ''Mississippi Historical Society''. Retrieved August 2, 2021.</ref> Later in 1957 when the Senate took up the [[Civil Rights Act of 1957|Civil Rights Act]] that year, Murray joined the majority of his Democrat colleagues (including the Southern [[segregation]]ists) in voting for the removal of Title III<ref>[https://www.govtrack.us/congress/votes/85-1957/s71 HR. 6127. CIVIL RIGHTS ACT OF 1957. AMENDMENT TO DELETE AUTHORITY FOR ATTORNEY GENERAL TO SEEK PREVENTIVE RELIEF IN CIVIL RIGHTS CASES UNDER THE 14TH AMENDMENT.]. ''GovTrack.us''. Retrieved August 2, 2021.</ref> as well as instituting a jury trial amendment,<ref>[https://www.govtrack.us/congress/votes/85-1957/s73 HR. 6127. CIVIL RIGHTS ACT OF 1957. AMENDMENT TO GUARANTEE JURY TRIALS IN ALL CASES OF CRIMINAL CONTEMPT AND PROVIDE UNIFORM METHODS FOR SELECTING FEDERAL COURT JURIES.]. ''GovTrack.us''. Retrieved August 2, 2021.</ref> both of which watered down the legislation to being effectively toothless.