The riot on Sunday night local time, only three years after similar violence killed 74 people, began ahead of a match between Egyptian Premier League clubs Zamalek and ENPPI at Air Defence Stadium east of Cairo.
Such attacks in the past have sparked days of violent protests pitting the country's hard-core fans against police officers in a nation already on edge after years of revolt and turmoil.
A statement from Egypt's public prosecutor said the violence killed 22 people and that it had ordered an investigation.
What caused the violence wasn't immediately clear. Security officials said Zamalek fans tried to force their way into the match without tickets, sparking clashes.
Zamalek fans, known as White Knights, posted on their group's official Facebook page that the violence began because authorities only opened one narrow, barbed-wire door to let them in.
They said that sparked pushing and shoving that later saw police officers fire tear gas and birdshot.
A fan who tried to attend the game, who spoke to the Associated Press on condition of anonymity out of fear of being targeted by police, said the stampede was caused by police who fired tear gas at the tightly packed crowd.
"Those who fell down could not get back up again," the man said.
The Zamalek fan group later posted pictures on Facebook it claimed were of dead fans, including the names of 22 people it said had been killed.
The AP could not immediately verify the images, nor the casualty count.
Egypt's hardcore soccer fans, known as Ultras, frequently clash with police inside and outside of stadiums.
They are deeply politicised and many participated in the country's 2011 uprising that forced out President Hosni Mubarak.
Many consider them as one of the most organised movements in Egypt after the Islamist Muslim Brotherhood, which the government later outlawed as a terrorist organisation following the 2013 military overthrow of Islamist President Muhammad Morsi.
The violence comes as police face increasing scrutiny following the shooting death of a female protester in Cairo and the arrest of protesters under a law heavily restricting demonstrations.
President Abdel-Fattah el-Sissi has pledged to bring stability to Egypt amid bombings and attacks by Islamic militants, but also has said Egypt's emergency situation meant that some violations of human rights were inevitable, if regrettable.
The deadliest riot in Egypt soccer history came during a 2012 match when Port Said's Al-Masry team hosted Cairo's Al-Ahly.
That riot, at the time the deadliest worldwide since 1996, killed 74 people, mostly Al-Ahly fans.
Two police officers later received 15-year prison sentences for gross negligence and failure to stop the Port Said killings, a rare incident of security officials being held responsible for deaths in the country.
Seven other officers were acquitted, angering soccer fans who wanted more police officers to be held accountable for the incident and other episodes of violence.
In response, angry fans burned down the headquarters of Egypt's Football Association, also protesting its decision to resume matches before bringing those behind that 2012 riot to justice.
They have also protested and fought officers outside of the country's Interior Ministry, which oversees police in the country.