Rabbi Ephraim ben Aharon Navon was born in 5437 (1677) in Constantinople, into the Navon family, according to the Chida's Shem HaGedolim and Rabbi Chaim Shmuel Danon's introduction to the Machaneh Ephraim; others say he was born in Nicopol, Bulgaria, and that his family moved to Constantinople shortly afterwards. There he studied Torah with his friend of the same age, the gaon Rabbi Yaakov Sasson, under their teacher Rabbi Alfandari, and distinguished himself early by his diligence and insight.

Around 5460-5461 (1700) he went up to Eretz Israel and settled in Jerusalem. According to some versions, including the Shem HaGedolim, he had already married the daughter of Rabbi Yehudah Ergas and went up together with his father-in-law; according to Rabbi Chaim Shmuel Danon's introduction, he went alone and married after his arrival. In Jerusalem he was received with honor and admiration; Rabbi Chaim Shmuel Danon wrote: "When our master went up from Constantinople to Jerusalem, all the people rejoiced with great joy: a lion has come up, whose Torah proclaims his greatness." During his first ten years in the city he studied in seclusion and without interruption, covering the entire Talmud in depth as well as the Rambam and the Beit Yosef, most likely at the Neveh Shalom yeshiva founded by Rabbi Yitzchak de Mayo. His fame then spread throughout the Jewish world.

The Jews of Jerusalem were suffering at the time from heavy oppression by the Ottoman authorities: taxes, fines and persecutions drove many of them to flee, but Rabbi Ephraim remained, almost the only Jewish leader in the city. When the situation became unbearable, he left Jerusalem as an emissary (shadar) of the community. Arriving in Constantinople, he won the esteem of its scholars, who urged him to stay, and Rabbi Yehudah Rosanes, av beit din of the city and author of the Mishneh LaMelech, appointed him halachic authority and dayan. Rabbi Avraham Rosanes wrote of him: "From day to night his mouth did not cease from study... his heart was like the heart of a lion to resolve the halachah, and the paths of the whole Talmud were clear to him."

His work, the Machaneh Ephraim, follows the order of the Rambam's Mishneh Torah and deals, often in question-and-answer form, with questions of talmudic civil law such as the waiver of a debt (mechilah), asmachta, or the obligations of an unwitting thief. He did not live to see it printed: on his deathbed he asked his son Rabbi Yehudah Navon, author of Kiryat Melech Rav, to publish it, which he did in Constantinople in 5498 (1738). The Chida wrote: "his wisdom and erudition are evident from his awesome book," and the Chatam Sofer praised its renown "among all the books of the Sephardic sages, the great Acharonim." The book, with the glosses of Rabbi Akiva Eiger, is still studied in yeshivot.

Rabbi Ephraim Navon passed away in Constantinople at the age of 58, on Monday, 26 Nissan 5495 (1735), as recorded on his tombstone, which was rediscovered in 5657 (1897) by his descendant Yosef Navon Bey after having been lost for more than 150 years. He left a line of sages and dayanim; his great-grandson Rabbi Yehudah Navon served as Rishon LeTzion.