The 73-year-old veteran leader is the second president of Djibouti since it gained independence from France in 1977.
Results show his rival, businessman Zakaria Farah, took less than 5,000 votes.
Farah cast doubt on the transparency of the voting process, saying his delegates were not present at polling stations.
“My vote is of no use, nor are the votes of 80 percent of the Djiboutian people,” the opposition candidate told AFP news agency in a text message.
The electoral campaign was lacklustre, reported RFI's French Africa service.
Opposition marches took place in working class areas and the arrest of opposition supporters was regularly criticised, although the president’s rallies took place without incident.
215,000 were eligible to vote (out of a population of 990,000), in one of the 529 polling stations, mostly located in the capital.
On Friday evening, the prime minister Abdoulkader Kamil Mohamed announced on Facebook that "the participation would be more than 77 percent," compared to 68 percent in 2016.
In a social media post early on Saturday, Guelleh wrote, “Thank you for your trust, thank you for Djibouti! Together, let’s continue!”
His predicted fifth term will be his last under a 2010 constitutional reform that scrapped term limits while introducing an age limit of 75, which would lock him out of future elections.
Djibouti is a strategically important country in the Horn of Africa that hosts several foreign militaries.
It is bordered by Somaliland, Ethiopia and Eritrea, and is the location for several ports and free trade zones, underlining its importance as a transportation and logistical hub.
The country’s economy shrank by 1 percent in 2020, but is expected to grow 7 percent this year, according to the International Monetary Fund.
Djibouti’s gross domestic product (GDP) per capita is about $3,500, higher than much of sub-Saharan Africa, but about 20 percent of the population lives in extreme poverty and 26 percent are unemployed, according to the World Bank.
