Palestinians threw stones and fireworks while police fired stun grenades after security forces entered the Al-Aqsa compound before briefly going inside the mosque itself.
Police said they went a few metres (yards) into the mosque to shut the doors in a bid to restore calm and lock in rioters who were inside.
About 300 security personnel had entered the compound when the clashes began with a couple of hundred Palestinians, an AFP photographer reported.
It was the first time Israeli security forces had entered the mosque since November, when clashes with worshippers also erupted.
There were multiple casualties and arrests surrounding the clashes, which came as Jews sought to access the mosque compound on Tisha B'av, a day commemorating the destruction in ancient times of the first and second temples.
Palestinians were angered by what they considered intrusions by Jews. Visits are allowed, but Jewish prayer at the site is prohibited.
Tensions were already high after a Jewish woman publicly made insulting comments about the Prophet Mohammed last week.
"Masked rioters fled into the mosque and started to throw stones and blocks at police from inside Al-Aqsa mosque," police said in a statement.
"They threw fireworks directly at police ... In light of the severe confrontation and the escalating actions of the rioters and with the aim of preventing further injury to police...Forces entered a number of metres (yards) inside and closed the doors to the mosque with the rioters inside, restoring order."
Protests broke out in the lanes and alleyways of the Old City around the mosque, with demonstrators confronting police and chanting "Allahu Akbar" and police firing stun grenades.
Some vowed to protect Al-Aqsa, with one man saying the holy site "is in our blood.
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