He turned the country into one of the most repressive states in the world.
The acting president, Shavkat Mirziyoyev - who has also held on to his position as prime minister - will almost certainly win.
Uzbekistan has never had free and fair elections, and it is common for the incumbent to receive more than 90% of the vote.
Although Mr Mirziyoyev is running for the first time, being acting president gives him access to so-called "administrative resources" - which are often used to guarantee a landslide victory on polling day.
The three other candidates pose little challenge, even though two of them competed during the last election in 2015.
The head of the Senate was supposed to become the interim leader after the death of Mr Karimov. But he opted out in favour of Mr Mirziyoyev - illustrating who holds real power.
The leaders of neighbouring countries have also openly supported Mr Mirziyoyev's candidacy.
Islam Karimov's eldest daughter, Gulnara Karimova, was once among the most powerful people in the country, and regarded as a possible successor to her father.
But she fell from grace several years ago, when US and European authorities launched a corruption probe against her. Uzbekistan's prosecutors also named her in a separate investigation.
In the aftermath, she disappeared from the public eye. Some local media even reported that she has been poisoned and buried in an unmarked grave.
But her son, in a recent interview with the BBC, denied the rumours and claimed that she is still under house arrest in Tashkent.
Islam Karimov Jr told BBC Uzbek that the authorities may try to "eliminate" Ms Karimova by poisoning her.
"They are not interested in freeing her since they will have to answer a lot of questions then," he said.
Local media reports also suggest that the sons-in-law of would-be president Shavkat Mirziyoyev have begun taking over businesses belonging to the family - in this case, from the husband of Karimov's other daughter, Lola Tillayeva-Karimova.
BBC interview: 'Show the world my mum is alive'
To boost his popularity, Shavkat Mirziyoyev has reversed some of the unpopular policies adopted during the rule of Islam Karimov, and has begun improving tense relations with neighbouring countries.
He proposed and signed laws that have a clear populist agenda - on fighting corruption, improving protection of citizens' rights, and simplifying business registration.
He also suggested liberalising currency transactions - one of the most hated policies - as people cannot freely exchange currency in Uzbekistan.
But critics say these changes are just temporary moves to help Mirziyoyev gain legitimacy.
Maintaining the current repressive system would ensure that he stays in power, in the same way Islam Karimov remained as president for nearly three decades.
Once Mr Mirziyoyev fully consolidates power, analysts believe that he will use fear and coercion more openly in order to secure his presidency from any potential rivals.
However, there could still be some economic changes. Uzbekistan wants to attract foreign investment - which would help to ease social discontent.
The peaceful transition since the death of Islam Karimov suggests the political elite have already reached agreement. It is not in their interest to change a system they benefit from.
And one of Mr Mirziyoyev's possible rivals, deputy Prime Minister Rustam Azimov, has kept a low profile in recent months.
Once Mr Mirziyoyev is elected, his influence will only grow.
If his potential opponents do not act before the vote, then they are unlikely to openly challenge him after it.
Uzbekistan is voting to elect a new president following the death of Islam Karimov, the only leader the country has known since the fall of the Soviet Union.