The Tuesday appearance is the first briefing since press secretary Karoline Leavitt began maternity leave at the end of April.
The White House said Rubio will discuss Project Freedom's humanitarian successes and other foreign policy priorities as officials rotate through the podium during Leavitt's absence.
Rubio has become a prominent multitasker in the Trump administration, also serving as interim national security adviser after Michael Waltz's departure and previously holding acting USAID and archivist roles.
Could a legal challenge to Rubio's past appointment invalidate current national security decisions?
With military clashes escalating, can the US 'Project Freedom' remain a purely humanitarian mission?
How will the US blockade of Iranian ports impact already volatile global energy markets?