The Team Penske driver won the first stage in Iowa and came through multiple cautions to take the chequered flag after 350 laps.
Polesitter Kyle Larson and Denny Hamlin wrecked on lap 172 when a small correction put Daniel Suarez into the Busch Light Pole Award holder, who was then helpless as he slammed into Hamlin.
Blaney led for 201 laps - a personal record - and retook first position from Joey Logano with 84 laps to go, powering home from there to win by eight tenths of a second from William Byron.
"What a cool way to win here. This place means a lot to me, it means a lot to my mom, and we had a lot of people here tonight cheering us on, so they willed us to that one," Blaney told NBC Sports.
"Overall, I really appreciate the whole 12 boys. I mean, our car was really fast all night, and we got a little bit better through the night.
"Two tires was a good call there -- I didn't know how well it was gonna hold on, I kind of started to struggle a little bit at the end, but had enough to hang on. [It] makes up a little bit for a couple weeks ago."
Iowa is special. To have that many friends and family members on hand and get my 3rd different series win here…amazing. Can’t thank the 12-Team and Crew enough, we had a fast car and we hit all our marks. Thank you to all of our partners and supporters. pic.twitter.com/YWbRws18hB
Blaney now holds a spot on the NASCAR playoffs grid, where he will hope to become the first driver to win back-to-back championships in the current playoff format.
Chase Elliott claimed third, while Christopher Bell, and Ricky Stenhouse Jr. rounded out the top five.
Joey Logano, Josh Berry, Alex Bowman, Daniel Suarez, and Brad Keselowski followed them home to round out the top ten.