The Henotikon (the "act of union") was issued by Byzantine emperor Zeno I in 482, in an attempt to reconcile the differences between the supporters of Orthodoxy and Monophysitism.

In 482 the Patriarchate of Alexandria passed to Peter III , who proved to be a Monophysite, despite the condemnation of this christological opinion at the Council of Chalcedon. The Patriarch of Constantinople, Acacius, devised an eirenic formula of unity called the Henotikon, which Zeno promulgated without the approval of a synod of bishops as Church policy. By this act, Zeno hoped to placate the increasingly Monophysite provinces of Egypt, Palestine and Syria, which were under increasing attacks by the Persians.

The items the Henotikon endorsed included:

• the condemnations of Eutyches and Nestorius made at Chalcedon;
• an explicit approval of the twelve anathemas of Cyril of Alexandria; and
• it avoided stating whether Jesus had one or two natures, in an attempt to appease both Monophysite and Orthodox Christians.

This act failed to satisfy either side. All church leaders took offense at the Emperor's open dictate of church policy, although the Patriarchs of Antioch and Alexandria were pressured into subscribing to the Henotikon. After two years of prevarcation and temporializing by Acacius, Pope Felix III condemned the act and excommunicated Acacius (484), although this was largely ignored in Constantinople, even after the death of Acacius in 489.

Zeno died in 491. His successor Anastasius I was sympathetic to the Monophysites, but he accepted the Henotikon. However, Anastasius was unpopular because of his Monophysite beliefs, and Vitalian, a Chalcedonian general, attempted to overthrow him in 514. Anastasius then attempted to heal the schism with Pope Hormisdas, but this failed when Anastasius refused to recognize the excommunication of the now deceased Acacius. General Vitalian tried to overthrow the emperor for a second time, but he was defeated by loyal officers.

The schism caused by the Henotikon was officially settled in 519 when Emperor Justin I recognized the excommunication of Acacius and reunited the churches. However, the Patriarchs of Alexandria, Antioch, and Jerusalem now embraced Monophysitism. Although the orthodox churches of the East and West were now reunited, in practise they were already diverging, and continued to separate further over the next 500 years.