Eric David Harris was born on April 9, 1981, in Wichita, Kansas. Harris's parents were both born and raised in Colorado. His mother, Katherine Ann Poole, was a homemaker. His father, Wayne Harris, was working in the United States Air Force as a transport pilot, so their family moved a lot. In 1983, the family moved to Dayton, Ohio, when Harris was two years old. Six years later, the family relocated to Oscoda, Michigan. Michigan pastor William Stone lived across the street from the Harris family while they were located in Oscoda. Stone recalled them as "great neighbors" and often saw Wayne very engaged with his sons. The Harris family then moved to Plattsburgh, New York, in 1991. During his tenure at Stafford Middle School, Harris played Little League Baseball, regularly went to birthday parties and was "part of the crowd". Kyle Ross, a former classmate of Harris, said, "He was just a typical kid." The Harris family finally settled back in Colorado the next year when Wayne retired from the military.

On a 1997 English class assignment, Harris wrote about how difficult the move was from New York to Colorado. "It was the hardest moving from Plattsburgh. I have the most memories from there", Harris continued. "When I left (his friends) I felt alone, lost and even agitated that I had spent so much time with them and now I have to go because of something I can't stop." Harris, in a basement tape, blamed his father for moving the family around, forcing Harris to "start out at the bottom of the ladder."

The Harris family lived in rented accommodations for the first three years that they lived in the Littleton area. While Harris was in 7th grade, he met Klebold. In 1996, the Harris family purchased and settled at a house south of Columbine High School. Harris' older brother, Kevin, attended college at the University of Colorado. Harris' father took a job with Flight Safety Services Corporation and Harris' mother, a former homemaker, became a caterer.

Harris entered Columbine High School in 1995 as a freshman. Columbine had just gone through a major renovation and expansion. From all accounts, he had many friends and was left forward and mid-field on the Columbine soccer team for his freshman and sophomore year. According to one of his teammates, Josh Swanson, he said Harris was a "solid" soccer player, who enjoyed the sport a lot. During his freshman year, Harris met Tiffany Typher. They had German class together. Typher later recounted that Harris quickly wooed her. Harris asked her to homecoming and she accepted. After the event, it appeared that Typher was no longer interested in seeing Harris anymore, for reasons never disclosed.

On April 20, 1999, just weeks before Harris and Klebold were both due to graduate, Brooks Brown, who was smoking a cigarette outside during lunch break, saw Harris arrive at school. Brown had severed his friendship with Harris a year earlier after Harris had thrown a chunk of ice at his car windshield. Brown reconciled with Harris just prior to the shooting. Brown approached Harris near his car and scolded him for skipping his morning classes, because Harris was always serious about schoolwork and being on time. Harris replied, "It doesn't matter anymore." Harris followed up a few seconds later, "Brooks, I like you now. Get out of here. Go home." Brown, who felt uneasy, quickly left the school grounds. At 11:19 am, he heard the first gunshots after he had walked some distance away from the school, and informed the police via a neighbor's cell phone.

By that time, Klebold had already arrived at the school in a separate car, and the two boys left two duffel bags, each containing a 20-pound propane bomb, inside the cafeteria. Their original plans indicated that when these bombs detonated, Harris and Klebold would be waiting at their cars and would shoot, stab and throw bombs at survivors of the initial explosion as they ran out of the school. At noon, this would be followed by bombs set up in their personal cars detonating, killing first responders and others on scene. When these devices failed to detonate, Harris and Klebold resorted to gunning down their classmates and teachers. It was the deadliest attack ever perpetrated at an American high school until Nikolas Cruz committed the Parkland shooting on February 14, 2018. Harris was responsible for eight of the thirteen confirmed deaths (Rachel Scott, Daniel Rohrbough, teacher Dave Sanders, Steve Curnow, Cassie Bernall, Isaiah Shoels, Kelly Fleming, and Daniel Mauser), while Klebold was responsible for the remaining five (Kyle Velasquez, Matthew Kechter, Lauren Townsend, John Tomlin, and Corey DePooter). There were 24 injured (21 of them by the shooters), most in critical condition.

At 12:02 pm, Harris and Klebold returned to the library. Of the 56 library hostages, 34 remained unharmed, all of whom escaped after Harris and Klebold left the library initially. Investigators later found that Harris and Klebold had enough ammunition to have killed them all. This was 20 minutes after their lethal shooting spree had ended, leaving 12 students dead, one teacher dying, and another 24 students and staff injured. Ten of their victims had been killed in the library. It is believed they came back to the library to watch their car bombs detonate, which had been set up to explode at noon. This did not happen, as the aforementioned bombs failed. Harris and Klebold went to the west windows and opened fire on the police outside. No one was injured in the exchange. Between three and six minutes later, they walked to the bookshelves near a table where Patrick Ireland lay badly wounded and coming in and out of consciousness. Student Lisa Kreutz, injured in the earlier library attack, was also in the room, unable to move.

By 12:08 pm, Harris and Klebold had killed themselves. In a subsequent interview, Kreutz recalled hearing a comment such as, "You in the library", around this time. Harris sat down with his back to a bookshelf and fired his shotgun through the roof of his mouth; Klebold went down on his knees and shot himself in the left temple with his TEC-9. An article by The Rocky Mountain News stated that Patti Nielson overheard them shout "One! Two! Three!" in unison, just before a loud boom. Nielson said that she had never spoken with either of the writers of the article, and evidence suggests otherwise. Just before shooting himself, Klebold lit a Molotov cocktail on a nearby table, underneath which Ireland was lying, which caused the tabletop to momentarily catch fire. Underneath the scorched film of material was a piece of Harris's brain matter, suggesting Harris had shot himself by this point.