Marco Rubio arrived at the Vatican for an audience with Pope Leo XIV, Reuters reported, quoted by BTA.
According to the agency, the meeting could take place in a tense atmosphere due to Donald Trump's continued criticism of the Holy Father on topics such as the war in Iran and migration policy.
Rubio's motorcade passed through the center of Rome under increased security measures, and the closed-door conversation with the pontiff is expected to last about 30 minutes.
After the meeting, the US Secretary of State will also talk with Pietro Parolin.
Pope Leo XIV, who is the first US-born head of the Roman Catholic Church, has drawn criticism from Trump after his positions against US-Israeli actions towards Iran and Washington's tough anti-immigration policy.