The annual awards show, a key showcase event for the music industry, honored Timberlake with the top Billboard 200 album for last year's "The 20/20 Experience," the highest prize for an album at the show.
The 33-year-old pop singer, who is on tour in Europe and not in attendance, accepted the award in a taped speech with his touring band, leading them in a gospel and blues-tinged song of "Thank You."
But the top moment of the show so far was a performance of "Slave to the Rhythm" by late pop star Michael Jackson, whose likeness and dancing was rendered by a computer-generated imaging, prompting an emotional standing ovation from the crowd.
Seventeen-year-old pop sensation Lorde, dressed all in black with black feather fringes, captured the award for top new artist and top rock song for the hit "Royals," which already landed her two Grammy Awards earlier this year.
The teen, who has also won fans with her thoughtfulness and defiance towards traditional standards of Hollywood beauty, said she was grateful to be able to mature in the spotlight and for the "dialogue around my work and myself."
Imagine Dragons, who also performed their song "Tiptoe," won for top rock album while country singer Luke Bryan won for top country artist.
The Billboard Music Awards - which measures honors by sales, radio airplay, touring, streaming and other metrics - is a top venue for artists to unveil new songs in time for the summer.
The show's first hour featured eight performances, including from pop stars Katy Perry, Shakira, country duo Florida Georgia Line with country singer Luke Bryan, and Nickelodeon star Ariana Grande and Australian rapper Iggy Azalea.
Rapper Pitbull kicked off the show alongside Jennifer Lopez and Brazilian singer Claudia Leitte from the MGM Grand Garden Arena with a performance of "We Are One (Ole Ola)," the theme to next month's soccer World Cup in Brazil.
Lorde and Imagine Dragons are finalists in a leading 12 categories. Bruno Mars and Timberlake will go up against Imagine Dragons, Miley Cyrus and Perry for the top artist prize. Beyonce, Timberlake, Bryan and rappers Eminem and Drake are all finalists for album of the year.