"Thank God this is a good day; the day of participation and active involvement of our dear people in a significant national event: the elections," Ayatollah Khamenei said after casting his ballot at a polling station in Tehran.
"I have heard that people's passion and interest is higher than the first round. May God make it this way and if it is, it will be gratifying," Ayatollah Khamenei noted.
Polling places opened at 8 a.m. (0430 GMT) on Friday and will close at 6 p.m. (1430 GMT), but the Interior Ministry may extend this time if needed.
The runoff election is happening because no candidate won a clear majority in the June 28 vote.
"God willing, our dear people will be able to vote and choose the best," Ayatollah Khamenei said.
"At this stage, people should be more motivated to finish the job and have our president tomorrow," he said.
"May God help the nation succeed and prosper the country and make all those who are struggling in this way subject to his grace and mercy."
Candidates Masoud Pezeshkian and Saeed Jalili emerged as frontrunners, yet neither succeeded in obtaining an outright majority, necessitating the current runoff.
Pezeshkian has a background as a health minister and is a legislator from Tabriz in the northwest. Jalili holds experience as a diplomat and the chief nuclear negotiator.
This election will choose a new president after President Raeisi passed away in a helicopter crash on May 19.
Mohsen Eslami, the election headquarters spokesperson, said on Thursday that there are 58,640 polling stations, the same as before. He also said that early results could be announced by Saturday morning. The election headquarters has confirmed that 61 million people can vote.