His reign was dominated by the struggle with Ahmad ibn Ibrahim al-Ghazi during the Abyssinian-Adal war until Ahmad's defeat and death in the Battle of Wayna Daga on February 21, 1543. Gelawdewos devoted time and energy to rallying his people against Ahmad, a determination his chronicler credits prevented Ahmad's forcible conversions from being permanent. With Ahmad's death, Gelawdewos was not only able to eject the leaderless Muslim forces from the Ethiopian Highlands, but also from the lowlands to the east, which included the Sultanate of Dawaro and Bale. He also turned his attention to the numerous Ethiopians who had crossed over to the Imam's side, either to further themselves or out of self-preservation. While some presented themselves to Gelawdewos expecting to be pardoned only to be executed, to many others he granted his safe conduct, according to Miguel de Castanhoso, "for there were so many [who had joined Imam Ahmad] that had he ordered all to be killed, he would have remained alone.
Whilst Gelawdewos was campaigning in the west, Nur ibn Mujahid once again invaded. Gelawdewos's vassal Fanu'el succeeded in repulsing them. In 1550 the Emperor followed up with a further attack into Muslim territory, plundering the countryside for six months. At one point he captured Harar, where Barakat ibn Umar Din of the Adal Sultanate was killed, the last member of the Walashma dynasty. The Emperor further pushed the campaign into Adal, destroying castles and capturing livestock.
Emir Nur had the Emperor's head sent to the country of Sa'ad ad-Din II, then rode off to plunder Ethiopian territory before returning home. The explorer Richard Francis Burton tells a slightly different account, adding that Gelawdewos had been supervising the restoration of Debre Werq when he received a message from Emir Nur challenging him to combat. When the Emperor met the Emir, a priest warned that the angel Gabriel had told him Gelawdewos would needlessly risk his life—which caused most of the Ethiopian army to flee.
In the same letter, King John promised to send priests more worthy than Bermudes, and during his reign two different groups of Jesuit missionaries arrived in Ethiopia. The first group arrived 7 February 1555 to determine the state of the country and whether the Ethiopians would properly receive a Patriarch anointed by the Catholic Church. Gelawdewos received them, but gave them no overt encouragement. The second group landed in March 1557, and was headed by Andres de Oviedo, who had been made titular bishop of Nice. Gelawdewos received them just before leaving to campaign against Nur ibn Mujahid but did not make any promises.