Rabbi David Oppenheim was born in Worms in June 1664, the son of Rabbi Avraham Oppenheim, a rabbi and community leader, and nephew of the famous financier Samuel Oppenheimer, from whom he inherited a great fortune. He studied under Rabbi Gershon Ashkenazi in Metz, Rabbi Yitzchak Binyamin Wolf of Landsberg, Rabbi Yaakov Zak Ashkenazi, father of the Chacham Tzvi, and Rabbi Binyamin Wolf Epstein in Friedberg; as a young man he befriended Rabbi Yair Chaim Bacharach. In 1681 he married Gnendel, daughter of the court Jew Leffmann Behrends of Hanover.

Ordained at twenty, he was appointed in 1691, at twenty-five, rabbi of Nikolsburg and chief rabbi of Moravia. In 1703 he became chief rabbi of Prague, in 1713 of half of Moravia, and by 1718 of all Bohemia. His ties with the rulers of the Empire made him one of the most influential figures in Central European Jewry. He wrote some twenty works of halacha and aggadah, including the responsa Nishal David; his son-in-law was Rabbi Chaim Yona Teomim.

With his wealth he assembled the largest Jewish library of his time, gathering thousands of printed books and rare manuscripts. The collection is now held at the Bodleian Library in Oxford.

He passed away in Prague on 7 Tishrei 5497 (1736) and rests in the city's Old Jewish Cemetery.