Voting began at 6:00 a.m. local time (0300 GMT) Friday after weeks of campaigning in the tiny east African country.
The 63-year old President Guelleh, who ruled the country since 1999, seeks his third term while former chief of the country's Constitutional Commission, Mohamed Warsama Ragueh, runs as an independent.
The two opposition parties are boycotting the election saying the polls will not be free and fair.
The opposition parties have failed to agree on a single candidate to run against President Guelleh, who promised the vote will be a clean one as international election monitors are observing the polls.
Djibouti, which lies in the Horn of Africa, is strategically located at the western gateway of the Red Sea and the Gulf of Aden. Population is estimated to be a little over 850,000.
The former French colony is bordered by Eritrea to the north, Ethiopia to the west and south, while war-torn Somalia lies to the southeast. The horn of African nation has largely remained peaceful since independence in 1977.