Around 1,500 residents of nearby illegal settlements, protected by Israeli soldiers, descended on Joseph's Tomb - sacred to mainstream Jews as well as Samaritans, Muslims and Christians - late on Wednesday, the Israeli army said.
Dozens of Palestinians gathered at the scene in protest at the incursion, with youths throwing stones at the heavily armed delegation of settlers.
Local media report that two journalists were among the 20 Palestinians injured when soldiers opened fire with live ammunition, rubber-coated steel bullets and tear gas.
The Israeli military blamed local residents for the "riot".
"At the entrance of the city of Nablus a violent riot was instigated during which Palestinians hurled rocks and firebombs," an army spokeswoman said.
She said the army had used "riot dispersal means" to break up the protest.
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An Israeli army bulldozer caught fire after Palestinians apparently threw Molotov cocktails at it, videos published by local media appeared to show.
The army said no soldiers were injured.
The tomb is deep inside the occupied West Bank, territory that is supposed to form a key part of a future Palestinian state.
It has been the scene of repeated clashes and was torched in October 2015 before being repaired later.
The site is inside Area A, where the PA is meant to have full administrative and security control, but the Israeli military frequently ignores the terms of the Oslo Accords and accompanies ultra-orthodox and nationalist Jewish groups on visits to the tomb, while prohibiting local Muslims from worshipping there.
51 years of illegal occupation
Israel has occupied the West Bank with its military since 1967, committing daily crimes against Palestinian civilians.
More than 600,000 Israeli Jews live in settlements in the occupied West Bank and East Jerusalem, in constructions considered illegal under international law.
Along with appropriating land, occupying Israeli forces and settlers routinely torment Palestinians in Nablus, notably graffiti-spraying "death to Arabs" on Palestinian property.
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