Güyük received military training and served as an officer under Genghis Khan and Ögedei Khan. He married Oghul Qaimish of the Merkit clan. In 1233, Güyük, along with his maternal cousin Alchidai and the Mongol general Tangghud, conquered the short-lived Dongxia Kingdom of Puxian Wannu, who was a rebellious Jin official, in a few months. After the death of Tolui, Ögedei proposed that Sorghaghtani, the widow of Tolui, marry his son Güyük. Sorghaghtani declined, saying that her prime responsibility was to her own sons.
Güyük participated in the invasion of Russia and Central Europe in 1236–1241 with other Mongol princes, including his cousin Batu and half-brother Kadan. He led his corps in the Siege of Ryazan and the lengthy siege of the Ossetian capital Maghas. During the course of the conquest, Güyük quarreled violently with Batu at the victory banquet and screamed at him, "Batu is just an old woman with a quiver". Güyük and Büri, a grandson of Chagatai, stormed out of the banquet and rode away swearing and cursing. When word reached the Great Khan, they were recalled for a time to Mongolia. Ögedei refused to see them and threatened to have his son Güyük executed. Ögedei calmed down and finally admitted Güyük into his ger. Ögedei criticized Güyük, "Do you think that the Russians surrendered because how mean you were to your own men. ...Because you captured one or two warriors, you think that you won the war. But you didn't capture even a single kid goat." Ögedei reprimanded his son harshly for fighting within the family and for mistreating his soldiers. Güyük was dispatched again to Europe.
In the meantime, Ögedei had died (in 1241), and his widow Töregene had taken over as regent, a position of great influence and authority that she used to advocate for her son Güyük. Batu withdrew from Europe so that he might have some influence over the succession, but despite his delaying tactics, Töregene succeeded in getting Güyük elected Khan in 1246. When Genghis Khan's youngest brother, Temüge, threatened the Great Khatun Toregene in an attempt to seize the throne, Güyük came to Mongolia from Emil to secure his position immediately.
Güyük's enthronement on 24 August 1246, near the Mongol capital at Karakorum, was attended by a large number of foreign ambassadors: the Franciscan friar and envoy of Pope Innocent IV, John of Plano Carpini; Grand Duke Yaroslav II of Vladimir; the incumbents for the throne of Georgia; the brother of the king of Armenia and historian, Sempad the Constable; the future Seljuk Sultan of Rum, Kilij Arslan IV; and ambassadors of the Abbasid Caliph Al-Musta'sim and Ala ud din Masud of the Delhi Sultanate. According to John of Plano Carpini, Güyük's formal election in a great kurultai, or diet of the tribes, took place while his company was at a camp called Sira Orda, or "Yellow Pavilion," along with 3,000 to 4,000 visitors from all parts of Asia and eastern Europe, bearing homage, tribute, and presents. They afterwards witnessed the formal enthronement at another camp in the vicinity called the "Golden Ordu," after which they were presented to the emperor. Mosul submitted to him, sending envoys to that assembly.
When the papal envoy John of Plano Carpini protested Mongol attacks on the Catholic kingdoms of Europe, Güyük stated that these people had slain Mongol envoys in the time of Genghis Khan and Ogedei Khan. He also claimed that "from the rising of the sun to its setting, all the lands have been made subject to the Great Khan", proclaiming an explicit ideology of world conquest. The Khagan wrote a letter to Pope Innocent IV on the relations between the Church and the Mongols. "You must say with a sincere heart: 'We will be your subjects; we will give you our strength'. You must in person come with your kings, all together, without exception, to render us service and pay us homage. Only then will we acknowledge your submission. And if you do not follow the order of God, and go against our orders, we will know you as our enemy." According to the account by John of Plano Carpini, Genghis Khan's daughter or the aunt of the Khagan was executed for poisoning Ogedei.
Güyük followed his father's policy and had Fatima arrested and executed for bewitching his brother Koden (Khuden) and Abd-ur-Rahman was also beheaded for corruption. Of the provincial officials appointed under Toregene, only the Oirat official Arghun Aqa remained. Güyük had Temüge's case investigated by Orda Khan and Möngke, and they had him executed. Güyük replaced the child khan Qara Hülëgü of the Chagatai Khanate with his favorite cousin Yesü Möngke to secure his position. He also restored his father's officials, Mahmud Yalavach, Masud Beg and Chinqai to positions in the provinces.
Güyük reversed several unpopular edicts of his mother the regent and made a surprisingly capable khan, appointing Eljigidei in Persia in preparation for an attack on Baghdad and the Ismailis and pursuing the war against the Song Dynasty. He was, nevertheless, insecure and won the disapproval of his subjects by executing several high-ranking officials of the previous regime for treason. The Seljuk princes struggled incessantly for the throne of the Sultanate of Rum. Despised by Izz-ad-Din, Rukn ad-Din Kilij Arslan IV came to Mongolia. Güyük ordered Rukn ad-Din enthroned in Iz-ad-Din Kaykaus II's place. A darughachi with 2,000 Mongol troops was sent to enforce this decision. When both David Narin and David Ulu summoned before Güyük in Karakorum, he made David Ulu the senior king and divided the Kingdom of Georgia between them. After the treaty signed by the Mongols and the Cilician Armenia in 1243, the king Hetoum I sent his brother Sempad to the Mongol court in Karakorum and made a formal agreement in 1247 in which Cilician Armenia would be considered a vassal state of the Mongol Empire. Due to Armenia's voluntary surrender, Sempad received a Mongol wife, and his kingdom was spared Mongol overseers and tax. Güyük demanded full-submission of the Abbasids and the Ismailis. Güyük Khan blamed Baiju for the irritated resistance of the Abbasid Caliphate.