In a message read by the director of Khamenei's office, he said: "I endorse the vote (for) the wise, honest, popular and scholarly Mr Pezeshkian, and I am appointing him as the president of the Islamic Republic of Iran".
The new president is due to be sworn in before parliament on Tuesday.
The endorsement ceremony was held in the capital Tehran in the presence of senior Iranian officials and foreign diplomats, and broadcast on state TV.
Pezeshkian won a runoff election on July 5 against the ultraconservative Saeed Jalili to replace president Ebrahim Raisi who died in a helicopter crash in May.
The 69-year-old reformist secured more than 16 million votes, or about 54 percent of the roughly 30 million ballots cast.
Turnout in the runoff election stood at 49.8 percent, up from a record low of about 40 percent in the first round, according to Iran's electoral authority.
Jalili attended Sunday's ceremony, as did former moderate president Hassan Rouhani who had backed Pezeshkian's presidential bid along with Iran's main reformist coalition.
Pezeshkian was the only candidate representing Iran's reformist camp allowed to stand in the election, for which all contenders were approved by the conservative-dominated Guardian Council.
Iran's president is not head of state, and the ultimate authority rests with the supreme leader -- a post held by Khamenei for the last 35 years.
Following Khamenei's official endorsement, Pezeshkian thanked the leader and the Iranian people, vowing to carry the "heavy burden" of the presidency.
The election came against a backdrop of heightened regional tensions since the Gaza war began in early October, disputes with Western powers over Iran's nuclear programme, and domestic discontent over the state of the sanctions-hit economy.
On the campaign trail, Pezeshkian had pledged to try to revive a 2015 nuclear deal with the United States and other world powers, which imposed curbs on Iran's nuclear activity in return for sanctions relief.
The deal collapsed in 2018 after Washington withdrew from it.
Pezeshkian has in a recent article called for "constructive relations" with European countries, even though he accused them of reneging on commitments to mitigate the impact of US sanctions.
Pezeshkian is a heart surgeon who has represented the northwestern city of Tabriz in parliament since 2008.
He served as health minister under Iran's last reformist president Mohammad Khatami, who held office from 1997 to 2005.
