Lotti was born in Venice or Hanover (where his father, Matteo, was Kapellmeister). After studying with Giovanni Legrenzi, Lotti made his career at St Mark's Cathedral in Venice, first as an alto singer, then as assistant to the second organist, then as second organist, then (from 1704) as first organist and finally (from 1736) as maestro di cappella, a position he held until his death. He also wrote music for, and taught at, the Ospedale degli Incurabili. In 1717 he was given leave to go to Dresden, where a number of his operas were produced. He returned to Venice in 1719 and remained there until his death in 1740.
Lotti wrote in a variety of forms, producing masseses, cantatas, madrigals, around thirty operas and instrumental music. His sacred choral works are often unaccompanied (a cappella). His work is considered a bridge between the established Baroque and emerging Classical styles.
Lotti was a notable teacher, with Domenico Alberti, Benedetto Marcello, Baldassare Galuppi and Jan Dismas Zelenka among his pupils. He was married to the noted soprano, Santa Stella.