The kingdom's Eastern Province has been hit by previous attempts by Sunni extremists to foment sectarian tensions with its large Shiite community, including a deadly shooting in November.
The interior ministry said a large explosion hit the mosque in Kudeih in Shiite-majority Qatif district during the main weekly prayers.
An activist said at least four worshippers were killed and others wounded, and news websites in eastern Saudi Arabia posted photographs of bodies lying in pools of blood.
An interior ministry spokesman said an investigation has been opened and more details of the explosion would follow.
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Saudi police have made a string of arrests in recent months of Sunni extremists suspected of plotting attacks aimed at stirring sectarian unrest in confessionally divided Eastern Province.
Most of Saudi Arabia's minority Shiites live in the east, where they have long complained of marginalisation in the Sunni-dominated kingdom.
Last November, gunmen killed seven Shiites, including children, in the eastern town of Al-Dalwa during the commemoration of Ashura, one of the holiest occasions of their faith.
Last month, the interior ministry said it had dismantled a 65-strong cell with suspected links to the Islamic State jihadist group in Iraq and Syria that was implicated in a plot to "incite sectarian sedition" through similar attacks.
Since 2011, protests and sporadic attacks on security forces have occurred in Shiite areas, leaving about 20 Shiite youths dead.