Trump, a Republican, had nominated Chase Johnson for the position of inspector general for the Federal Communications Commission, and Eris Soskin for the same position at the Department of Transportation.
The Senate voted 39-48 for each nominee.
Sen. Kamala Harris (D-Calif.), the Democratic vice presidential nominee, and 12 Republican senators missed the votes.
The GOP holds a 53-47 majority in the Senate.
Senate Majority Leader Mitch McConnell (R-Ky.) joined Democrats in voting no, a move that lets him bring the nominations to a vote again in the future.
The Republican senators who missed the vote were Roy Blunt of Missouri, Richard Burr of North Carolina, Ted Cruz of Texas, Mike Enzi of Wyoming, Jodi Ernst of Iowa, Deb Fischer of Nebraska, Kelly Loeffler of Georgia, Rand Paul of Kentucky, David Perdue of Georgia, Rob Portman of Ohio, James Risch of Idaho, and Mike Rounds of South Dakota.
“We don’t have 12 Republicans here, so we’re going to lose all these votes,” Sen. Josh Hawley (R-Mo.) told reporters, adding: “All I can say is I hope they’re having a good weekend.”
The Senate rarely meets on weekends but was in session as legislators try to hammer out compromises on next year’s government funding and a fresh COVID-19 relief package.
The Senate confirmed two other nominations, Thompson Dietz to be a judge on the U.S. Court of Federal Claims for 15 years, and Beth Harwell to be a member of the Board of Directors of the Tennessee Valley Authority for a term expiring May 18, 2024.
A number of Democrats joined Republicans in voting for Dietz and Harwell, including Sens. Mark Kelly (D-Ariz.), Sheldon Whitehouse (D-R.I.), and Mark Warner (D-Va.).
No Republicans voted against either nominee.