In the first round of the 2021 MLB Draft, 17 of the 36 selections were NCAA Division I players.
The top two picks were college players. The Pittsburgh Pirates took Louisville catcher Henry Davis with the No. 1 pick. The Texas Rangers made Vanderbilt pitcher Jack Leiter the second selection.
Players were selected from 16 different schools. Vanderbilt was the only school with multiple selections, as right-hander Kumar Rocker was taken No. 10 by the New York Mets.
There were four players taken from the ACC and SEC as well as two from the Big 12.
| Rd. | Pick | Team | Player | School | Pos. |
| 1 | 1 | Pittsburgh | Henry Davis | Louisville | C |
| 1 | 2 | Texas | Jack Leiter | Vanderbilt | RHP |
| 1 | 5 | Baltimore | Colton Cowser | Sam Houston | OF |
| 1 | 9 | California | Sam Bachman | Miami (Ohio) | RHP |
| 1 | 10 | NY Mets | Kumar Rocker | Vanderbilt | RHP |
| 1 | 14 | San Francisco | Will Bednar | Mississippi State | RHP |
| 1 | 15 | Milwaukee | Sal Frelick | Boston College | OF |
| 1 | 17 | Cincinnati | Matt McClain | UCLA | SS |
| 1 | 18 | St. Louis | Michael McGreevy | UCSB | RHP |
| 1 | 19 | Toronto | Gunnar Hoglund | Ole Miss | RHP |
| 1 | 20 | NY Yankees | Trey Sweeney | Eastern Illinois | SS |
| 1 | 21 | Chicago Cubs | Jordan Wicks | Kansas State | LHP |
| 1 | 23 | Cleveland | Gavin Williams | East Carolina | RHP |
| 1 | 24 | Atlanta | Ryan Cusick | Wake Forest | RHP |
| 1 | 32 | Detroit | Ty Madden | Texas | RHP |
| 1 | 33 | Milwaukee | Tyler Black | Wright State | 2B |
| 1 | 35 | Cincinnati | Matheu Nelson | Florida State | C |