In 2017, Spithill skippered LDV Comanche to win Line Honours in the Rolex Sydney Hobart Yacht Race.

[2] He debuted in the America's Cup in 2000 with Young Australia, showing his precocious talent despite leading an antiquated boat.

For the 2007 America's Cup, Spithill was chosen by Francesco De Angelis, whom he had beaten in the 2003 Louis Vuitton quarter-finals, as his heir as helmsman of Luna Rossa Challenge.

Spithill was a mainstay of the team, which he led to the final of the Louis Vuitton Cup 2007 after beating one of the favourites, Oracle BMW Racing, 5–1 in the semifinals.

He earned the nickname of "James Pitbull" among Italian fans because of his aggressive tactics during the pre-start phase of the races.

In the 2017 America's Cup defence held in Bermuda, he also led Oracle Team USA, but lost eight races to one.