On October 28, 1880, Tombstone town marshal Fred White attempted to break up a group of five late-night, drunken revelers shooting at the moon on Allen Street. Deputy Sheriff Earp went to assist White. As he approached, he saw White attempt to disarm Curly Bill Brocius. The gun discharged, striking White in the groin. He died of his wound two days after the shooting. Wyatt escorted Brocius to Tucson to stand trial. Although the shooting was eventually ruled accidental, Brocius held a grudge against the Earps for the rest of his life.

During the heyday of San Diego's boom, Earp won a racehorse named Otto Rex, after which he and his wife Josie began to travel the racehorse circuit. In Santa Rosa, Earp personally competed in and won a harness race.

When he moved to Tombstone in 1879, Wyatt brought horses and a buckboard wagon which he planned to convert into a stagecoach, but he found two established stage lines already running. He later said that he made most of his money in Tombstone as a professional gambler.

At the scene of the holdup, Wyatt discovered an unusual boot print left by someone wearing a custom-repaired boot heel. He checked a shoe repair shop in Bisbee known to provide widened boot heels and was able to link the boot print to Stilwell.

Wyatt had offered an unknown sum of money to Ike Clanton if he would provide information leading to the capture or death of certain Cowboys involved in a stagecoach robbery. Although Ike was initially interested, he began threatening the Earps when word of his supposed cooperation leaked, threatening his standing with the Cowboys. The night before the famous gunfight, he told Wyatt that the fighting talk had been going on for a long time and he intended to put an end to it, swearing "I will be ready for you in the morning."

A well-known city ordinance required McLaury to deposit his pistol upon arrival in town. When Wyatt demanded, "Are you heeled or not?", McLaury said he was not armed, but Wyatt saw a revolver in plain sight on Tom's right hip. Witnesses say Wyatt drew his revolver from his coat pocket and pistol whipped McLaury with it twice, leaving him prostrate and bleeding on the street. Saloon-keeper Andrew Mehan testified that he afterwards saw McLaury deposit a revolver at the Capital Saloon.

After the gunfight, Wyatt testified, "Billy Clanton leveled his pistol at me, but I did not aim at him. I knew that Frank McLaury had the reputation of being a good shot and a dangerous man, and I aimed at Frank McLaury." Though Wyatt wounded McLaury with a shot in the stomach, Frank managed to get off a few shots before collapsing.

Four days after the shootout, Ike Clanton filed murder charges. Wyatt and Doc Holliday were arrested and brought before a Justice of the Peace, but the charges were eventually dropped, and the lawmen were shown to have acted within the law.

Morgan Earp was murdered on March 18, 1882, while playing billiards, shot by gunmen firing from a dark alley through a window into the billiard room. The bullet shattered his spine, and he died 40 minutes later.

The coroner reports credit the Earp posse with killing Frank Stilwell, Curly Bill, Indian Charlie, and Johnny Barnes during their two-week-long vendetta ride.