Anti-Shi'ism, also known as Shiaphobia, is hatred of, prejudice against, discrimination against, persecution of, and violence against Shia Muslims because of their religious beliefs, traditions, and cultural heritage. The term was first used by Shia Rights Watch in 2011, but it has been used in informal research and written in scholarly articles for decades.

The dispute over who was the rightful successor to Muhammad resulted in the formation of two main branches, the Sunni, and the Shia. The Sunni, or the "followers of the way", followed the caliphate and maintained the premise that any member of the Quraysh tribe could potentially become the successor to Muhammad if he was accepted by the majority of Muslims. The Shia instead consider the Ahl al-Bayt (household of Muhammad) and maintain the view that only God can decide who His hujjah (proof) can be. This is due to many reasons, including every successor to a prophet being chosen by God from Adam all the way to Muhammad. This includes leaders (Qur'an 5:12), Prophets, messengers, Imams (Qur'an 2:124) and righteous woman (Qur'an 3:42). It is believed that Ali ibn Abi Talib was chosen by God through Muhammad (Hadith of the pond of Khumm) which is also known as Ghadir Khumm where he becomes Muhammad's successor, thus Ali became the religious authority for the Shia people. Militarily established and holding control over the Umayyad government, many Sunni rulers perceived the Shia as a threat – to both their political and religious authority.

The Sunni rulers under the Umayyads sought to marginalize the Shia minority. Throughout the history of Islam, the persecution of Shias by their Sunni co-religionists has often been characterized by brutal and genocidal acts; the most recent case of religious persecution by Sunni Muslim militants involved the genocidal massacre, ethnic cleansing and forced conversion of Shias to Sunni Islam by ISIL in Syria and Iraq (2014–2017). Comprising around 10% of the entire world's Muslim population, to this day, the Shia remain a marginalized community in many Sunni dominated countries and in those countries, they do not have the right to freely practice their religion or establish themselves as an organized denomination.

On the other hand, Sunni and Shia Muslims have lived together in peace over the years. In many countries, they have prayed in the same mosques, while having distinct rituals. Shia identitarianism was based on victimhood narrative of alleged intolerance from mainstream Sunnis who historically questioned their loyalty and Islamic credentials as well as over verdicts of Takfir from hardline Sunnis who denounces all Shias as apostates.

The grandson of Muhammad, Imam Hussein, refused to accept Yazid I's rule. Soon after in 680 CE, Yazid sent thousands of Umayyad troops to lay siege to Hussein's caravan. During the Battle of Karbala, after holding off the Umayyad troops for six days, Hussein and his 72 companions were killed, beheaded, and their heads were sent back to the caliph in Damascus. These 72 included Hussein's friends and family. The more notable of these characters are Habib (Hussein's elderly friend), Abbas (Hussein's loyal brother), Akbar (Hussein's 18-year-old son), and Asghar (Hussein's six-month-old infant). On the night of Ashura (which is called Sham-e-Gharibaan), the army of Yazid burned the tents which Hussein's family and friends had lived in. The only occupants of the tents after the war were the women, children, of Hussein's companions along with Hussein's last ill son named Zain-Ul-Abideen (who became the next Imam after Hussein). During the raid, Yazid's forces looted, burned, and tortured the women and children. They then took the heads of the dead, planting them on spearheads to parade. The women's shawls and headdresses were also stripped and they were forced to march beside their men's heads all the way to Damascus. They stayed in prison there for about a year. While Imam Hussein's death ended the prospect of a direct challenge to the Umayyad caliphate, it also made it easier for Shiism to gain ground as a form of moral resistance to the Umayyads and their demands.

In 1029 Mahmud of Ghazni conducted a brutal campaign against the city of Rayy. As a stauch Sunni orthodox, he crucified a large number of Ismailis together with Mazdakites and burned many Shi'ite books whose teachings he considered heretical. The poet Farrukhi Sistani wrote two related qasida poems, in which he depicted Rayy as a worthy target for a ghazi raid and those who disobey God to be infidels or heretic (kafirs, babd-madhhabi). During the rule of the Seljuks, large numbers of Ismailis are thought to have converted in hopes of evading persecution.

After the Mongol sack of Baghdad in 1258, prejudice against Shias became more frequent, reminiscent of blaming Shias for every problem. One statement states that a Shia minister had betrayed the empire by exposing their weaknesses to the Mongols.

In response to the support of Alevis and Alawites to the Shia Safavid empire, who were converting the Sunni Iran to Shia along with cursing the first three Rashidun caliphs and burning the tombs of Sunni saints, the Ottoman Empire persecuted Alevis in Anatolia. Tens of thousands of Shias were killed in the Ottoman Empire, including the Alevis in Turkey, the Alawis in Syria and the Shi'a of Iraq and Lebanon.