Upon the death of Emperor Dawit, his older brother Tewodros ordered Zara Yaqob confined on Amba Geshen (around 1414). Despite this, Zara Yaqob's supporters kept him a perennial candidate for Emperor, helped by the rapid succession of his older brothers to the throne over the next 20 years, and left him as the oldest qualified candidate. David Buxton points out the effect that his forced seclusion had on his personality, "deprived of all contact with ordinary people or ordinary life." Thrust into a position of leadership "with no experience of the affairs of state, he [Zara Yaqob] was faced by a kingdom seething with plots and rebellions, a Church riven with heresies, and outside enemies constantly threatening invasion." Buxton continues,
- In the circumstances it was hardly possible for the new king to show adaptability or tolerance or diplomatic skill, which are the fruit of long experience in human relationships. Confronted with a desperate and chaotic situation he met it instead with grim determination and implacable ferocity. Towards the end of his life, forfeiting the affection and loyalty even of his courtiers and family he became a lonely figure, isolated by suspicion and mistrust. But, in spite of all, the name of this great defender of the faith is one of the most memorable in Ethiopian history.
Although he became Emperor in 1434, Zara Yaqob was not crowned until 1436 at Axum, where he resided for three years. It was not unusual for Ethiopian rulers to postpone their coronation until later in their reigns.
After he became Emperor, Zara Yaqob married princess Eleni, who had converted from Islam before their marriage. Eleni was the daughter of the king of Hadiya, one of the Sidamo kingdoms south of the Abay River. Although she failed to bear him any children, Eleni grew into a powerful political person. When a conspiracy involving one of his Bitwodeds came to light, Zara Yaqob reacted by appointing his two daughters, Medhan Zamada and Berhan Zamada, to these two offices. According to the Chronicle of his reign, the Emperor also appointed his daughters and nieces as governors over eight of his provinces. These appointments were not successful.
He defeated Badlay ad-Din, the Sultan of Adal at the Battle of Gomit in 1445, which consolidated his hold over the Sidamo kingdoms in the south, as well as the weak Muslim kingdoms beyond the Awash River. Similar campaigns in the north against the Agaw and the Falasha were not as successful.
After witnessing a bright light in the sky (which most historians have identified as Halley's Comet, visible in Ethiopia in 1456), Zara Yaqob founded Debre Berhan and made it his capital for the remainder of his reign.
In his later years, Zara Yaqob became more despotic. When Takla Hawariat, abbot of Dabra Libanos, criticized Yaqob's beatings and murder of men, the emperor had the abbot himself beaten and imprisoned, where he died after few months. Zara Yaqob was convinced of a plot against him in 1453, which led to more brutal actions. He increasingly became convinced that his wife and children were plotting against him, and had several of them beaten. Seyon Morgasa, the mother of the future emperor Baeda Maryam I, died from this mistreatment in 1462, which led to a complete break between son and father. Eventually relations between the two were repaired, and Zara Yaqob publicly designated Baeda Maryam as his successor.