It was not immediately clear what sparked the violence. The Islamic endowment that administers the site said Israeli police entered in force shortly after early morning prayers, when thousands of worshippers were at the mosque.
Videos circulating online showed Palestinians hurling rocks and police firing tear gas and stun grenades.
The Palestinian Red Crescent emergency service said it evacuated 20 wounded people to hospitals. The endowment said one of the guards at the site was shot in the eye with a rubber bullet.
The mosque is the third holiest site in Islam. It is built on a hilltop that is the most sacred site for Jews, who refer to it as the Temple Mount. It has been a major flashpoint for Israeli-Palestinian violence for decades.
Tensions have soared in recent weeks following a series of deadly attacks by Palestinians that killed 14 people inside Israel. Israel has carried out a wave of arrests and military operations in the occupied West Bank, setting off clashes in which several Palestinians have been killed.
Tens of thousands of Palestinians were expected to gather at Al-Aqsa for Friday prayers, as Muslims observe the holy month of Ramadan.
Weeks of protests and clashes in Jerusalem during Ramadan last year eventually ignited an 11-day Gaza war.
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