He first practised as a physician and officiated as a Jewish preacher at Livorno, Italy. There he wrote in Italian a work entitled "Paschologia" (Cologne, 1702), in which he dealt with the differences of calculation in the calendars of the Greek, Roman, and Jewish churches, and demonstrated the errors which had crept into the calendar from the First Council of Nicaea until 1692. In 1702 Nieto succeeded Solomon Ayllon as ecclesiastical chief of the Portuguese Jews in London.
And two years after his settlement in that city he published his theological treatise, Della Divina Providencia, ó sea Naturalezza Universal, ó Natura Naturante (London, 1704).
He explained that "nature" was a modern word, and in reality referred to the action of God in governing natural phenomena. Tzvi Ashkenazi, who was called in as arbitrator, decided in his favor (Hakham Tzvi, Responsa, Number 18).
Not only was he exonerated, but he was highly praised for his teachings. Nieto was also highly praised by Rabbi Chaim Azulay (the "Chida").
He died in London. Nieto was a powerful controversialist.
A prolific writer, his connection with Christian scholars was extensive, especially with Ungar, the bibliographer. Nieto was the first to fix the time for the beginning of Sabbath eve for the latitude of England.
In his Matteh Dan, or Kuzari Heleq Sheni (London, 1714), written in Hebrew and Spanish on the model of the Kuzari of Judah ha-Levi, he defended the Oral Torah against the Karaites, and showed that the disagreements in the Talmud lay not in essential laws but in minor matters.