Supporters of the defendants tried to storm the prison holding them and attacked police stations.
The 21 were sentenced over riots which killed 74 people after a football game at Port Said stadium last February.
Saturday’s violence follows a day of unrest on the second anniversary of the uprising that ousted Hosni Mubarak.
Egypt’s national defence council, which is headed by President Mohamed Morsi, has condemned the violence and called for dialogue, saying it would consider declaring a curfew in affected areas if necessary.
Thousands of people had taken to the streets on Friday to voice their opposition to the Islamist president, accusing him of betraying the revolution.
At least seven people were killed and more than 450 wounded in unrest across Egypt.
All 21 defendants sentenced to death on Saturday were fans of Port Said club al-Masry. When the verdicts were announced by a judge in the Cairo court, relatives of victims cheered.
However, the ruling caused supporters of the defendants to go on a rampage in Port Said. Two police officers were shot dead outside the city’s prison and the state security building was reportedly set on fire.
At least another 28 people were killed and about 300 were wounded in further clashes, officials said.
Two footballers were among those killed in Saturday’s clashes, state news agency Mena reported. They are former al-Masry goalkeeper Tamir al-Fahlah and Muhammad al-Dadhawi, a player for a lower-division Port Said club.
The violence continued despite the deployment of army units on the city’s streets.
Meanwhile, in Cairo, clashes also broke out between police and protesters near Egypt’s Interior Ministry. Police fired tear gas to try to prevent them from reaching the building.
Last year’s football riots led to the suspension of the league.
They began minutes after the game, when al-Masry fans invaded the pitch, hurling stones and fireworks at visiting supporters from Cairo club al-Ahly.
A section of al-Ahly supporters, known as the “ultras”, played a prominent role in the protests against ex-President Mubarak.
Some accused supporters of the toppled leader of instigating the Port Said violence. They also accused police of doing little to prevent the violence.
Seventy-three people, including nine policemen, were tried over the stadium clashes. None are al-Ahly fans.
The judge said he would announce verdicts for the remaining defendants on March 9.
Friday saw a big anti-government rally in Cairo’s Tahrir Square, with opposition supporters clashing with police.
There was also unrest in 12 out of 27 of Egypt’s provinces. At least six of the deaths occurred in Suez.
In Ismailia, protesters set fire to the headquarters of the Freedom and Justice Party, the political arm of the Muslim Brotherhood. The city’s governorate headquarters was later also stormed.
The liberal opposition accuses Mohamed Morsi of being autocratic and driving through a new constitution that does not protect adequately freedom of expression or religion.
The government is also being blamed for a deepening economic crisis.
One of the demonstrators at Cairo’s Tahrir Square, Momen Asour, said he had come to demand an end to President Mohamed Morsi’s rule.
“We have not seen anything. Neither freedom, nor social justice, or any solution to unemployment, or any investment,” he said.
“On the contrary, the economy has collapsed.”
President Mohamed Morsi and his allies have dismissed the claim, saying they have a democratic mandate following recent elections. The constitution, drawn up by an Islamist-dominated body, was approved by a referendum last month.
Port Said 2012 football deaths
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