More than 12,100 polling centers opened across Syria at 7:00 a.m. local time (0400 GMT) on Wednesday and will close at 7:00 p.m. local time (1600 GMT).
Results are expected to be announced by Friday evening.
On May 20, Syrian refugees and expatriates cast an early ballot in the embassies of their host countries.
Interior Minister Mohammad Khaled al-Rahmoun said that a total of 18 million Syrians at home and abroad were officially eligible to vote in the election.
Incumbent President Bashar al-Assad is widely expected to win a fourth seven-year term in a contest with former deputy cabinet minister Abdullah Sallum Abdullah and Mahmoud Ahmad Marei, head of the Arab Organization for Human Rights.
Assad cast his vote at a polling station in the city of Douma near the capital Damascus.
He told reporters that he did not give any weight to Western opinions about the validity of Syria’s presidential race, saying, “The value of these opinions is zero.”
In the 2014 poll, Assad secured almost 89 percent of the votes on a turnout of over 73 percent.
Interior Ministry has formed “rooms of operations” to follow up the election’s progress, deal with complaints and ensure its safety, Syria’s official SANA news agency reported.
Upon an invitation by the Syrian Parliament, delegations from the legislatures of “friendly and brotherly countries” such as Iran and Iraq traveled to Syria to help inspect the vote, the report added.
Syria has been gripped by foreign-sponsored militancy since March 2011. The Damascus government says the Western states and their regional allies are aiding Takfiri terrorist groups that are wreaking havoc in the Arab country.
In a statement released on Tuesday, the foreign ministers of France, Germany, Italy, Britain and the United States claimed that Syria’s presidential election “will neither be free nor fair.”