Six candidates are vying for the top job but the clear frontrunner is Guelleh, who is running for a fourth straight term in the former French colony. He took over from his uncle Hassan Gouled Aptidon who ruled from independence in 1977 until 1999.
There are some 180,000 registered voters out of a population of 875,000. The results are expected as early as Friday evening.
Djibouti is little more than a port with a country attached but has leveraged its position at the entrance to the Red Sea and one of the world's busiest shipping routes to attract powers such as the US, France and China who see it as a prime location for military bases to protect commercial and other interests.
Guelleh, 68, and his Union for the Presidential Majority (UMP) face a fractious opposition with his two main opponents -- Mohamed Daoud Chehem and Omar Elmi Khaireh -- both claiming to represent the Union for National Salvation opposition coalition.
The seven-party opposition alliance was founded in January 2013 but has failed to agree on a single candidate to contest its first presidential election, while three of the member parties have broken ranks to boycott the poll.
- No competition -
Guelleh won the last polls in 2011 with 80 percent of the vote, after parliament changed the constitution to clear the way for a third, and now a likely fourth, term.
Following parliamentary elections in 2013 which Guelleh's UMP won with 49 percent amid furious opposition claims of fraud, rival parties had demanded the creation of an independent electoral commission, a key element of a 2014 pact to resolve a political deadlock and end street protests.
Under that deal, the opposition agreed to accept just 10 members of parliament -- instead of the 52 they claimed to have won -- in return for a pledge that the government would set up an independent election body and ensure more rights for opposition parties.
But the commission was not created.
"We are not deluded. As of today, they even know what margin the president will win by," said Daher Ahmed Farah, leader of the Movement for Democratic Renewal which is boycotting Friday's vote.
The opposition has complained of curbs on freedom of assembly and expression during the campaign period since late March, with opposition candidate
Khaireh saying one of his rallies was blocked earlier this week.
Human rights organisations have also denounced political repression, pointing to the December 21, 2015 killing of 27 people by police.
Djibouti has launched major infrastructure projects -- including new ports, railways and oil and gas facilities -- aimed at turning it into a regional hub for trade and services.
- Boom for whom? -
"We are in phase of accelerated growth and the country needs Guelleh to ensure stability while completing all the economic development work started 10 years ago," said government spokesman Mahamoud Ali Youssouf.
To finance these projects, Djibouti has largely turned to loans from China, widening its public debt which could reach 80 percent of GDP in 2017, according to the International Monetary Fund.
But despite these big ticket schemes and economic growth of around 6 percent in 2014, there has been little improvement in the lives of ordinary people.
Three-fifths of the total population are unemployed and close to 80 percent live below the poverty line.
Social discontent is strong.
"It would be nice to have an equal distribution of wealth... We need more equity," said Alas, a Djibouti City resident who did not give his full name.
But the risk of upheaval remains low with Guelleh maintaining a tight grip with the tacit backing of France, the US and others who view him as a handy ally to protect their commercial and military interests.