Carl Edwards dominated most of the race with 160 laps led, but during the last round of pit stops with 35 laps remaining, Busch came out of pits first and took the lead for good, while Edwards exited fourth after a slow stop.
Edwards made a hard-charging effort in the closing laps, but Busch held him off at the finish by 0.7 seconds for his record-extending 51st career win in NASCAR's second-tier series. Eight of those wins have come this season.
"[Crew chief] Jason Ratcliff and these guys just keep digging," said Busch, who led 74 laps for his fourth Nationwide win at Richmond. "The guys on pit road and Jason making all the adjustments tonight were flawless."
Two weeks ago at Bristol, Busch surpassed Mark Martin for most career wins in the series.
Edwards endured a tire mishap during his final stop.
"I think we had a little bit of trouble with the right-front tire," he said.
Ricky Stenhouse Jr. finished third, which allowed him to widen his points lead as well as collect the $100,000 "Dash 4 Cash" bonus award from series title sponsor Nationwide Insurance. He was the highest finisher among the four eligible drivers for the cash award.
"I felt we had a little bit for Kyle there at the end," Stenhouse said. "It started out really good, and I was kind of running him down, but I lost some forward grip."
Ryan Truex finished fourth, while Kenny Wallace completed the top-five.
With seven races to go this season, Stenhouse holds a 16-point advantage over Sadler. Sorenson is now 45 points behind.
The 250-lap race at Richmond featured its share of accidents, and frustrations ran high at times.
Just after a restart on lap 79, Brad Keselowski, the pole sitter, shot up the track and brushed the wall. While Keselowski's incident occurred, Kevin Harvick hit Jason Leffler from behind and punted him into the wall.
Leffler, who was furious with Harvick, returned to the track after spending 80 laps in the garage for repairs. Harvick also took out Trevor Bayne late in the race.
"I just made a mistake by getting in there too fast, and then I got into the back of [Leffler] and turned him around," Harvick said. "He had a right to be mad. It was my fault. I tried to take my time and get around him, but he brake-checked me down there. I had to check up, and the 16 [Bayne] got into the back of me. A couple of laps later, the 16 got me into the fence with the right-rear and the right-front. As I came off the wall, I turned him."
Bayne, who had been running among the top-10 for most of the race, wound up finishing 28th. Harvick, the defending race winner, finished one lap down in 20th.
"It's pretty frustrating," Bayne said. "Harvick has always raced me well, but I don't know what happened tonight."
Keselowski made contact with the wall for the second time when Danica Patrick bumped into him just past the halfway point. Keselowski finished 19th, one spot behind Patrick, who competed in a stock car race at Richmond for the first time.