Dixon got out of the pits ahead of Vitor Meira on the final round of stops, then held off the Brazilian and hard-luck Marco Andretti to win the first 500 since the two warring open-wheel series came together under the IndyCar banner.
Danica Patrick failed to finish for the first time in four trips to Indy, though it wasn't her fault. She was clipped on pit road by Ryan Briscoe with 29 laps to go, breaking the left rear suspension on a car that had run in the top 10 most of the race but never seriously challenged for the lead. She finished 22nd.
Patrick's mishap was one of numerous crashes and mechanical failures that kept the race under yellow eight times for a total of 69 laps. But Dixon, who started from the pole, clearly had the strongest car on the track.
"There were so many yellows," Dixon said, "it was really hard to get into a rhythm."
Meira, driving for the one-car, low-budget Panther Racing team, has never won an IndyCar race but finished runner-up in the biggest race of all for the second time in four years.
Andretti appeared to knock teammate Tony Kanaan out of the race with an aggressive move just past the midway point, but all he got was another close call for a family that is now 1-for-57 at the Brickyard. The 21-year-old settled for third.
Dixon led 115 of the 200 laps and Chip Ganassi Racing teammate Dan Wheldon was out front for 30 more, backing up the speed they had shown all through the month of May.
"You're clear now," Dixon's spotter screamed over the radio as the 27-year-old New Zealander cleared the last group of lapped cars with two turns to go. "Bring it home! Bring it home!"
For a while, it looked as though an Andretti might finally break through to give the star-crossed family its first Indy victory since grandfather Mario won in 1969. Instead, it was the eighth time Marco, father Michael or Mario finished second or third.
Marco led twice for 15 laps, but the Andretti Green Racing -- co-owned by Michael -- made a crucial miscalculation on its last pit stop. They adjusted the rear wing, looking for more speed, but the No. 26 car wound up falling back in the closing laps.
"I think it was a team decision to do what we did," Marco said. "OK, we missed. So we messed up as a team. So move on."