Rabbi Yossi ben Chalafta, a Tanna of the fourth generation, was born in Tzippori, the son of Rabbi Chalafta, one of the city's leading sages, who had still seen Rabban Gamliel the Elder. He was one of the greatest disciples of Rabbi Akiva, his principal teacher, and also learned from his father, Rabbi Yehoshua, Rabbi Yishmael, Rabban Gamliel and others. He was one of the five students ordained by Rabbi Yehuda ben Bava at the risk of his life, at a time when the Romans had banned semicha.

A companion of Rabbi Yehuda and Rabbi Shimon, he was the teacher of Rabbi Yehuda HaNasi. He lived in Tzippori, where he earned his living as a tanner and instituted halachic ordinances; "Follow the sages to their academy… follow Rabbi Yossi to Tzippori," teaches the Talmud. The "Rabbi Yossi" quoted without qualification in the Mishnah is always he, and his opinions generally prevail in halacha.

He is the author of Seder Olam, the traditional chronology of Jewish history from Creation. The Talmud relates that he once entered a ruin in Jerusalem to pray, and that Elijah the Prophet appeared to him and taught him that God Himself weeps over the destruction of the Temple whenever Israel prays.

As early as the twelfth century, the traveller Yaakov ben Netanel HaKohen described his tomb, beside that of his father Abba Chalafta, at the site of today's village of Kfar Chananya in Galilee.