The monestary was established in 1416 by Tsong Khapa's disciple Jamyang Qoigyi, who was versed in both Esoteric and Exotoric Buddhism and became the first Kampo there. With the support of plutocrats, it developed as the richest monastery of Gelugpa and became the mother temple of Dalai Lamas. In 1546, the third Dalai was welcomed as the first Living Buddha into the monastery. At the invitation of Mongolia's king, he went to Qinghai Province to preach. He was dignified with the title 'the third Dalai Lama' the first and second Dalai were entitled, too. It is the very place that the second, third, and the fourth Dalai Lama held the Sitting-in-Bed Ceremony, as well as the residence of the fifth Dalai before his nomination by the government of the Qing Dynasty (1644 - 1911).

The ground of the monastery is organized on the caves and temples for Jamyang Qoigyi, together with two magnificent white pagodas. The buildings of the monastery are centered on these pagodas, The major buildings are Ganden Potrang, Coqen Hall, the four Zhacangs (or Tantric colleges), and Kamcuns.

The Ganden Potrang, in the southwest corner of the monastery, was built under the supervision of the second Dalai Lama Gendun Gyaco around the year of 1530. It became the residence of the second, third, fourth, and the fifth Dalai Lamas. After the fifth Dalai Lama moved to the Potala Palace, it was served as the meeting place for the local regime for both politics and religion. 

Sera, one of the three largest monasteries of Gelugpa, sits at the foothills of Tatipu. It is as prestigious as Drepung and Ganden, which both have longer histories. Sera, in Tibetan, means "Wild Rose Garden" since opulent wild rose woods once grew around it. A legend says that Tsong Khapa and his two disciples traveled in the area, spreading their religion. One day, they heard a horse whinnying underground when they were taking a walk in the rose woods. They dug up a statue of Hynagriva (a horse-headed demon-god) and Tsong Khapa began construction of a monastery to enshrine Hynagriva. However, the truth is that in 1414, Jamchen Chojey (or Sakya Yeshe), one of Tsong Khapa's disciples, visited Emperor Chengzu as Tsong Khapa's emissary. The Emperor Chengzu granted him a title of Dharma King of Great Mercy, sutras, and a set of sandalwood Arhats. In order to preserve them, Tsong Khapa instructed Jamchen Chojey to build a monastery to house the treasures. The Sera monastery was completed in 1419.

Sera is designed around a Main Assembly Hall, or Tshomchen in Tibetan, which is the grandest hall of Sera, occupying a floor space of 1,000 square meters. The four-storied hall has four chapels in which Arhats, Manjushri, Tsong Khapa, and Chenrezi are enshrined. Later, a huge Maitreya was enshrined in the hall during the reign of the Seventh Dalai Lama. The valuable Buddhist sutras that Jamchen Chojey brought back from Beijing are kept in a sutra pigeonhole adjacent to the hall.

Situated in Dranang, Samye Monastery was completed in 779 under the patron of Trisong Detsen. At the time of Samye's construction, Buddhism had been transmitted into Tibet, but there were no formal Buddhist priests or rituals. Trisong Detsen decided to invite Santarakshita and Padmasambhava, both Buddhist figureheads in India, to promote Buddhism in Tibet and participate in the construction of a monastery. Padmasambhava chose the construction site while the design was done by Santarakshita. After the construction was completed, Buddhism became the official religion in Tibet. Learned monks from inland China and India were invited to Tibet to translate Buddhist sutras into Tibetan. Trisong Detsen selected seven nobles to be the first monks in Tibet. Samye became the first formal monastery that established "triratna", referring to the Buddha, the Dharma and the Sangha, or Buddhist priesthood.

Samye means "unimaginable" in Tibetan. It was said that when Tritsong Detsen asked for suggestions about the construction of the monastery, Padmasambhava, exerting his magic power, showed the king an image of a monastery in his palm. That is the origin of the name.

The monastery combines the styles of China, Tibet and India, and the layout was designed to represent the ideal universe described in Buddhist scriptures. "Utse", the Great Hall symbolizing "Sumeru" in perfect Buddhist universe, is the largest structure in the monastery. The Sun and Moon chapels encircle the large hall, and four "stupas" of different styles stand at each corner of the room. These "stupas" are colored in red, white, black and green to represent the four Heavenly Kings. Four larger halls and eight smaller ones, evenly distributed around "Utse," represent the oceans in that universe. The monastery is secluded from the outside world by a circular wall with thousands of Buddha statues sitting on it. This wall represents a mountain near the border of the universe.