Rabbi Yitzchak was one of the principal disciples of Rabbi Shimon bar Yochai and one of the sages most often quoted in the Zohar. According to the Ohr HaChammah commentary on the introduction to the Zohar, he was one of the ten members of the Chevraya, Rabbi Shimon's circle of study, together with Rabbi Elazar, Rabbi Abba, Rabbi Chiya, Rabbi Yehuda and Rabbi Yossi.

He took part in the assembly of the Idra Rabba, at which three of the companions passed away; Rabbi Yitzchak was among those who remained. Rabbi Chaim Vital refers to him as "Rabbi Yitzchak Nafcha, mentioned in the Idra Rabba of Parashat Naso."

The Zohar (Parashat Vayechi) relates that one day Rabbi Yitzchak sat sadly at the door of Rabbi Yehuda, sensing that his end was near. Rabbi Shimon saw the angel of death dancing before him; he rose, took Rabbi Yitzchak by the hand and decreed that only those accustomed to come to him would enter, so the angel remained outside. According to this account and its commentators, Rabbi Shimon interceded for him and undertook to take him along at his own passing; the Ohr HaChammah accordingly writes that Rabbi Yitzchak departed this world together with Rabbi Shimon.

Rabbi Chaim Vital, based on what the Arizal revealed to him, places his grave in the valley descending west of Tzfat, on the mountainside facing the rock beneath which Rabbi Nechunya ben HaKana is buried, at the place known today as Wadi Amud below Tzfat. His son Rabbi Shmuel Vital adds that Rabbi Yitzchak is therefore not buried in Meron beside Rabbi Shimon and Rabbi Elazar, contrary to the popular belief.