The two killed were shot by police trying to disperse angry crowds in the city of Suez, medical officials said.
In the capital Cairo, thousands of protesters remained on the streets following a day of clashes with police.
Thousands marched to the interior ministry, where security forces fired tear gas to keep them back.
Earlier, the Egyptian prime minister announced the sackings of several senior officials.
The deaths came when fans invaded the pitch after a fixture between top Cairo club al-Ahly and the Port Said side al-Masry.
As night fell in Cairo, several thousand demonstrators remained in the streets around the interior ministry, witnesses said.
In Suez, health official Mohammed Lasheen said two people had been shot dead early on Friday.
A witness quoted by Reuters said: “Protesters are trying to break into the Suez police station and police are now firing live ammunition.”
Throughout Thursday, al-Ahly supporters gathered outside the club’s stadium in Cairo. A series of protest marches moved towards Tahrir Square, and then on to the ministry of interior.
Some chanted slogans against Egypt’s military rulers, while others threw stones.
“Our army must choose between the military council and the revolutionaries,” they chanted.
Police fired tear gas to keep the thousands of protesters away from the ministry, which is protected by concrete barricades.
Motorcycles ferried the injured from the scene as ambulances were often unable to get through.
At one point, ambulances intervened to rescue riot police whose vehicle mistakenly turned into a street full of protesters, Reuters reported.
Egyptian state news agency Mena quoted a health ministry official as saying 388 protesters were injured. Most of them were suffering from tear gas inhalation as well as bruises and broken bones from rocks.
A section of Al-Ahly supporters known as the “ultras” played a prominent role in last year’s street protests which led to the overthrow of President Hosni Mubarak.
The ultras believe they were targeted for their support for the revolution over the past year.
They accuse the police of deliberately allowing al-Masry fans to attack them.
“It’s like war, you can’t believe it. What happened yesterday [Wednesday] was war, it’s not football. To kill without any feeling… is not normal,” said former al-Ahly player Hani Seddik.
There were also protests in Port Said, Associated Press news agency reported.
Earlier on Thursday, parliament met in emergency session, beginning with a minute’s silence.
Port Said’s director of security and the head of investigations were suspended and are now in custody, Kamal al-Ganzouri said.
The government has come under renewed attack over its handling, both of the football game, and of the way it is handling the transition to democracy, our correspondent says.
The president of al-Ahly, Hamid Hamdy, said his club would not take part in league games.
“I hope that the world understands the position of al-Ahly club, that we are going through a very difficult time as a result of all of those martyrs that we lost yesterday,” he told a news conference.
“People should feel that there is a tragedy and a disaster which has happened in Egyptian sports, and for al-Ahly.”
Police in Egypt have been keeping a much lower profile since last year’s popular protests.
The Muslim Brotherhood – which has emerged as Egypt’s biggest party in recent elections – blamed ex-President Mubarak’s supporters for the violence.
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