Rabbi Yaakov Culi was born in Jerusalem around 5449 (1689) — around 1685 according to other sources — to a family descended from the Spanish exiles. His father, Rabbi Machir, was the son-in-law of Rabbi Moshe ibn Chaviv, and raised him from childhood to an ascetic life, content with little and sparing in sleep. Yaakov was the grandson and pupil of Rabbi Moshe ibn Chaviv.

His first undertaking was publishing his grandfather's writings. Having prepared them in Safed, he travelled in 5474 (1714) to Constantinople to print them. There he became close to the city's chief rabbi, Rabbi Yehudah Rosanes, then regarded as the highest authority of the East, who appointed him a dayan. In 1727 he published his grandfather's Shammot BaAretz. When Rabbi Yehudah Rosanes died that same year, Rabbi Yaakov was entrusted with putting his chaotic literary remains in order: he edited Parashat Derachim in 1728 and then Mishneh LaMelech, adding his own notes marked "amar hamagiah." He also published his grandfather's Ezrat Nashim, which opens with two of his own responsa.

His major work is Me'am Lo'ez, a vast encyclopedic commentary on the Torah in Judeo-Spanish (Ladino), drawn from the Talmud, Midrash and rabbinic literature. Rabbi Yehudah Mizrachi, a wealthy lover of Torah, funded the printing of a thousand copies of the volume on Bereishit. Rabbi Yaakov completed Genesis and Exodus up to chapter 24; after his death the work was continued by Rabbi Yitzchak Magreso and Rabbi Yitzchak Bechor Arguiti. The Chida wrote of him that he was "a swift scribe, expert in the Talmud, the codifiers and the commentators."

Works: Me'am Lo'ez (Genesis and part of Exodus), Mishneh Kesef on the Rambam (published in 5779), Simanim DeOraita, which remained in manuscript, as well as responsa and sermons printed with his grandfather's books.

He passed away in Constantinople on 19 Av 5492 (August 1732), before he could complete the Me'am Lo'ez.