For the next several years, he was regularly commissioned to write new operas practically every year for La Fenice and wrote more than a dozen comic operas and short farces for Venice. By 1796, he was a financial success and married a pupil, Angiola Venturali. She died in childbirth the next year, and in 1804, Mayr married her younger sister Lucrezia. In 1799, Mayr revised one of his Venetian operas, La Lodoiska, for production at La Scala. Its success led him, thereafter, to write most of his serious operas for that house, though he also wrote for Naples and other theaters. His Ginevra di Scozia premiered in Trieste in 1801. Its success made him one of the best-known names in Italian opera, with several of his major operas played in such centers as Vienna, Berlin, Weimar, Stuttgart, Warsaw, Dublin, London, New York, and Philadelphia. In 1802, Mayr became maestro di cappella of the cathedral in Bergamo and in 1805, director of the choir school there as well. He held those offices for the rest of his life. Early in the 1820s, Mayr developed cataracts and he wrote his last opera in 1824 before going completely blind by 1826. He founded the Philharmonic Society of Bergamo in 1822.
Mayr generally maintained the style and techniques of the previous generation of Neapolitan opera composers. He shows only minimal influence of composers such as Mozart, Haydn, or Beethoven, even though as a conductor and organizer of concerts he took care to introduce their music to Bergamo. However, in orchestration he was fairly innovative and introduced the technique of increasing loudness by piling on instruments, now generally known as the "Rossini crescendo," before Rossini did. His colorful instrumentation in many ways provided a basis for Rossinian and later nineteenth century opera. For the most part, his operas went entirely out of the repertoire before the first half of the nineteenth century was over and they are little heard. Still less-known are his more than 600 sacred works, for he insisted that they not be published.