Lee Petty, patriarch of a famous racing family whose most renowned member was his son Richard, won the first Daytona 500 on February 22, 1959 defeating Johnny Beauchamp in a highly unusual manner. Petty and Beauchamp were lapping the car of Joe Weatherly at the finish, when officials initially called Beauchamp the winner as the three cars crossed the line. After reviewing photographs and film of the finish for three days, the call was reversed, and Petty won the first Daytona 500.

The first rain-shortened Daytona 500 was the 1965 event. Leader Marvin Panch and Fred Lorenzen made contact on Lap 129, as rain began to fall; Panch spun out, and Lorenzen won when the race was finally called on Lap 133. The 1966 Daytona 500, won by Richard Petty, was also shortened to 198 laps due to rain.

During the start of the 1974 NASCAR season, many races had their distance cut ten percent in response to the energy crisis of the year. As a result, the 1974 Daytona 500, won by Richard Petty, was shortened to 180 laps (450 miles), as symbolically, the race "started" on Lap 21. The Twin 125 qualifying races were also shortened to 45 laps (112.5 miles).

In the 1976 Daytona 500, Richard Petty was leading on the last lap when he was passed on the backstretch by David Pearson. Petty tried to turn under Pearson coming off the final corner, but didn't clear Pearson. The contact caused the drivers to spin in to the grass in the infield just short of the finish line. Petty's car didn't start, but Pearson was able to drive his wrecked car just enough to limp over the finish line for the win.

The 1979 Daytona 500 was the first 500-mile race to be broadcast live on national television. (The Indianapolis 500 was only broadcast on a tape delay that evening during the time; most races were broadcast only through the final quarter to half of the race, as was the procedure for ABC's Championship Auto Racing broadcasts; with the new CBS contract, the network and NASCAR agreed to a full live broadcast.) A final lap crash and subsequent fight between leaders Cale Yarborough and Donnie Allison (along with Donnie's brother Bobby Allison) brought enough publicity to put NASCAR on the national radar. Donnie Allison was leading the race on the final lap with Yarborough drafting him tightly. As Yarborough attempted a slingshot pass at the end of the backstretch, Allison attempted to block him. Yarborough refused to give ground and as he pulled alongside Allison, his left side tires left the pavement and went into the wet and muddy infield grass. Yarborough lost control of his car and contacted Allison's car halfway down the backstretch. As both drivers tried to regain control, their cars made contact several more times before finally locking together and crashing into the outside wall in turn three. After the cars settled in the grass, Allison and Yarborough began to argue. After they had talked it out, Bobby Allison, who was lapped at that point, pulled over and began defending his brother, and a fight broke out. Richard Petty, who was over half a lap behind at the time of the crash, went on to win the race.

On the last turn of the final lap of the 2001 Daytona 500, NASCAR superstar Dale Earnhardt was killed in a crash. This was the second restrictor-plate race run under a rules package (discontinued after the 2001 season) that included a small strip atop the car's roof and a small lip on the rear spoiler. Though it was meant to give power back to the drivers and help produce more lead changes, critics charged that it created dangerous racing conditions. An 18-car crash on lap 173, which sent Tony Stewart's car flying end-over-end, caused the race to be red-flagged (stopped) while the track was made safe. Michael Waltrip, making his first start for Dale Earnhardt, Inc., won the race, with his teammate Dale Earnhardt, Jr. finishing second.

The 2001 Daytona 500 was also the first NASCAR Winston Cup (now Nextel Cup) points race to be televised by the Fox Network, which covered the other major Cup events during Speedweeks, as well as the previous day's Busch Series race. Fox's commentators and reporters included Darrell Waltrip, Michael's brother, and Larry McReynolds, who had been Dale Earnhardt's crew chief at the 1998 Daytona 500.

Sterling Marlin was battling Jeff Gordon for the lead of the 2002 Daytona 500 when they made contact. Gordon spun while a multi-car crash broke out behind them. NASCAR red-flagged the race so it could be raced to completion, and stopped the field on the backstretch. Marlin had been told that the right front fender on his car had been knocked into the right front tire, and jumped out of the car to pull the fender away from the tire. NASCAR officials in the safety vehicle immediately jumped out and stopped him. Since no one is allowed to work on a car during red-flag conditions, Marlin was sent to the back of the field. Marlin's move led to Ward Burton's win.

In 2003, Michael Waltrip won when rain shortened the race to 109 laps, and in 2004, Dale Earnhardt, Jr. won the race three years after his father's death and exactly six years to the date that his father won the Daytona 500.

Changes to the Daytona 500 meant the race could run into the dusk, with engines starting at 2:40 PM, and the green flag waving around 2:55 PM, meaning the race would finish under the lights as darkness fell at the finish. In 2005, Jeff Gordon won his third Daytona 500 in the first instance NASCAR used the green-white-checker finish rule in the 500. Jimmie Johnson took the honors in 2006, also under a nighttime green-white-checker finish.

Also in 2005, qualifying race distance was raised 20%, with the qualifying races now 60 laps (150 miles) and only the top two drivers making the field through the race under new NASCAR rules on exemptions.