He was drafted first overall by the Isles in the 2000 NHL Entry Draft, out of Boston University, prompting them to trade fellow young goaltender Roberto Luongo. DiPietro was the first goaltender ever to be selected with the number one overall pick in the draft, and was just the fourth American to occupy the top draft position.
Though his NHL debut was widely anticipated, and he played 20 games in the 2000-2001 season, he managed to post just 3 wins against 15 losses for a mediocre New York team and was sent to the minors for additional seasoning. He played for the Chicago Wolves of the IHL and the Bridgeport Sound Tigers of the AHL; he would play 10 games the next season before being called up for good in the 2003-2004 season.
The New York Newsday reported that the team offered him a 15-year contract in September 2005, but the League discouraged this, instead he signed a one-year offer. This left enough space under the new salary cap for the Islanders to re-sign winger Mark Parrish.
Over time, DiPietro has shown improvement in net, though he occasionally creates tense moments for Islander fans by leaving his net to play the puck. His goals-against average decreased from 3.49 in the 00-01 season to 2.36 in the 03-04 season. DiPietro plays a very different style from most NHL goaltenders, who generally stay in their goal crease the majority of the time to maximize their position when making saves. In certain situations, like on the power play, or when the puck ends up behind his goal net, DiPietro, arguably one of the best puckhandling goalies in the league, will leave his crease to play the puck up the boards and down the ice. The play could hit an open forward down the ice and spring odd-man rushes. In this role, albeit very risky, he's been likened to a "third" defenseman and has been compared in terms of puckhandling ability to goaltenders Martin Brodeur and Ed Belfour, who are also known as excellent puckhandling goalies.
Along with teammates Jason Blake and Mark Parrish, DiPietro was named to the US Olympic hockey team at the 2006 Torino Winter Olympics, held in February of 2006. DiPietro started the second game of the tournament against Kazakhstan, allowing one goal and picking up the win in Team USA's 4-1 victory.
He is a notable graduate of Saint Sebastian's School.
On September 12, 2006, DiPietro signed a 15-year, $67.5 million contract with the Islanders. It is considered to be the longest NHL official contract ever to be signed topping teammate Alexei Yashin's contract that was 10 years 
Played for United States in:
- World Junior Hockey Championship - 2000
- World Cup of Hockey - 2004
- IIHF World Championships - 2005
- XX Olympic Winter Games - 2006