Tsongkhapa began to teach while in his 20s, with his first teaching being on abhidharma (mdzod, special topics of knowledge). Everyone was astounded at his erudition. He also began to write and do more retreats. Soon, he had many disciples of his own. Although some accounts say Tsongkhapa took full monk vows at age 21, it is uncertain in which year this actually took place.

At one point, he studied and analyzed the entire Kangyur (bKa’-‘gyur) and Tangyur (bsTan-‘gyur) – the translated direct teachings of Buddha and their Indian commentaries. After that, at age 32, he wrote A Golden Rosary of Excellent Explanation (Legs-bshad gser-phreng), a commentary on Filigree of Realizations and thus on prajnaparamita. He synthesized and discussed all twenty-one Indian commentaries. Whatever he wrote, he substantiated with quotes from the entire span of Indian and Tibetan Buddhist literature, comparing and critically editing even different translations. Unlike previous scholars, he never shied away from explaining the most difficult and obscure passages in any text.
Together with Lama Umapa, Tsongkhapa did an extensive retreat on Manjushri. After the retreat, Tsongkhapa and his disciples restored a great Maitreya statue in Lhasa, which was the first of his four major deeds.
Tsongkhapa started The Gelug Sect in the late 14th century, following a period of religious reform. Tsongkhap was originally a monk of the Kargdam Sect. He went to the U-Tsang region to study the Buddhist scriptures in 1373, and combined features of other Tibetan Buddhist sects, such as the Sakya and Kagyu sects, in his new doctrine. He gave equal importance to esoteric and esoteric forms of Buddhism. Tsongkhapa strictly abided by the religious disciplines and set a good example for his followers. To show his difference from other monks and his determination to observe the commandments, Tsongkhapa began to wear a yellow hat. He wrote books to explain the Buddhist scriptures and did missionary work to spread the spirit of Buddhism, thus earning great respect among religious believers.

In 1409, Tsongkhapa constructed the Gandain Monastery in Dagze. He and his disciples recruited many followers to the temple, and formed the Gelug Sect. After the death of Tsongkhapa, his disciples established the Zhaibung Monastery, the Sera Monastery and the Zhaxilhunbu Monastery, as the influence of the Gelug Sect spread. The lofty spirit and rigorous study attitude of Tsongkhapa and his followers were highly appraised by monks of other Tibetan Buddhist sects, and many of them converted to the Gelug Sect. Most of the Gelug Sect monasteries were magnificent and housed large numbers of monks and exquisite Buddhist sculptures. They followed a strict scripture study system. The Gelug Sect grew to be the monst influential Tibetan Buddhist sect.