Nesar Jamyang Khyentse Wangchuk was born in Bodong E valley in 1524. His father was Namkha Dorje and his mother was Tseten Budren.

At the age of eight, he received his first vows from Gorampa. In the same year, he met Tsarchen Losal Gyatso. The following year, Tsarchen gave him initiations and sādhanas for a number of deities, including the Nine-deity Amitāyus and Hevajra. Jamyang Khyentse Wangchuk may have received this Vajrayoginī from him at the same time.

He received his novice vows when he was twelve. He studied until the age of twenty with Gorampa, Tsarchen, and Rutok Lachen. At the age of twenty, he received full ordination from these three masters. Khyentse Wangchuk received teachings from over thirty lamas of different traditions, and trained and practiced at many monasteries and hermitages.

At the instruction of Tsarchen Losal Gyatso, Khyentse Wangchuk went to Zhalu Monastery to receive teachings Gyalyum Wangmo. At the age of thirty-six, he was enthroned as the fourteenth abbot of Zhalu. He taught the Lamdré extensively, and also gave empowerments and teachings from the Kagyu and Nyingma traditions.

Jamyang Khyentse Wangchuk was an important author of ritual manuals and instructions. The sādhanas of Vajrayoginī that we commonly use today were written by this great master. Many of his sādhanas and explanations were included in famous collections of Jamyang Khyentse Wangpo and Jamyang Loter Wangpo.