In February 1962, the family moved to the United States, settling in Pasadena, California. Both Eddie and his older brother, Alex, are naturalized U.S. citizens. The brothers learned to play the piano as children starting at the age of six.

Van Halen revealed in an interview that he never could read the music. Instead, he learned from watching and listening. During recitals of Bach or Mozart, he would simply wing it. From 1964 through 1967, Edward won first place in the annual piano competition held at Long Beach City College. Afterward, the judges would comment that he had an interesting interpretation of the classical piece. Van Halen's view was, "What? I thought I was playing it correctly!" However, according to one interview, playing the piano did not prove to be challenging or interesting to him. Consequently, while Alex began playing the guitar, Eddie bought a drum kit and began practicing for hours every day.

Van Halen has used a variety of pickups including Gibson PAF's, 1970s Mighty Mites, DiMarzios and Ibanez Super 70s. He was using Mighty Mite pickups in 1977 club photos, just prior to the recording of the first Van Halen album. Mighty Mite pickups were OEM pickups made by Seymour Duncan and were copies of DiMarzio Super Distortion pickups. They can be identified by their lack of bobbin holes. Seymour Duncan started advertising pickup rewinding services in late 1977 to early 1978, and apparently rewound a Gibson PAF for Van Halen around the early 1978 period.

In 1972, Van Halen formed another band, originally called "Genesis". The name was changed to "Mammoth" when Van Halen became aware of the English progressive rock band of the same name.

Early Van Halen stage photographs, and demo and bootleg recordings from 1976 and before, do not indicate Van Halen using any tapping techniques. Comments about how he came across the tapping technique vary from interview to interview. In one review with Guitar World, he said:

The 1978 instrumental "Eruption" by Van Halen showcased a solo technique called tapping, using both left and right hands on the guitar neck. Although Van Halen popularized tapping, he did not, despite popular belief, invent the tapping technique. The tapping technique in blues and rock was picked up by various guitarists in the 1950s, 1960s and 1970s.

On August 29, 1980, Eddie met Actress Valerie Bertinelli at a Van Halen concert in Shreveport, Louisiana. They married in California on April 11, 1981; and have one child, a son, Wolfgang (born March 16, 1991).

In 1982, Van Halen was invited by Producer Quincy Jones to contribute the guitar solo for Michael Jackson's single "Beat It" but reportedly declined any payment for the recording, deeming a credit on the album sufficient.

Shortly afterwards, Van Halen released the album 1984, from which the single "Jump", was their first and only number-one single on the Billboard Hot 100. Other singles released from the album performed well, particularly "Hot for Teacher", the video for which featured a skimpily dressed model playing the part of a female elementary school Teacher and young actors portraying the band members as children. The album peaked at No. 2 on the Billboard charts, behind only Michael Jackson's Thriller.

In an interview in Guitar World magazine in July 1985, Van Halen states that his "brown sound" is "...basically a tone, a feeling that I'm always working at ... It comes from the person. If the person doesn't even know what that type of tone I'm talking about is, they can't really work towards it, can they?" In an interview with Billboard magazine in June 2015, he states that with the expression "brown sound" he actually tried to describe the sound of his brother Alex Van Halen's snare drum, which he thought "...sounds like he’s beating on a log. It’s very organic. So it wasn’t my brown sound. It was Alex's."

During Hagar's time with the band, some fans informally referred to the band as "Van Hagar" to distinguish it from the David Lee Roth lineup. With Hagar, all four studio releases reached No. 1 on the Billboard charts. For Unlawful Carnal Knowledge was awarded the 1992 Grammy Award for Best Hard Rock Performance with Vocal. The live album Live: Right Here, Right Now peaked at No. 5.

After his father's death in December 1986 and his brother Alex's eventual sobriety in April 1987, Eddie Van Halen struggled with drug and alcohol abuse on and off for twenty years. In April 1988, he was hospitalized with dengue fever, while on a wedding anniversary vacation in Australia. On September 2, 1994, he made his first attempt at sobriety.

The band auditioned many prospective replacements for Hagar, finally settling on Gary Cherone, former frontman of Boston hard rock band Extreme. Cherone predicted that the new lineup would last "10 years"; however, the Van Halen III (1998) album was poorly received. The band completed a world tour with their new single Without You and returned to the studio to start on a second album. However, Cherone soon after departed amicably and, without a lead singer, Van Halen went on hiatus.

Suffering from lingering injuries from past high-risk acrobatic stage antics and crashes, Van Halen underwent hip replacement surgery in November 1999, after his chronic avascular necrosis, with which he was diagnosed in 1995, became unbearable. In April 2001, Van Halen confirmed he had been undergoing treatment for tongue cancer since May 2000. The subsequent surgery removed roughly a third of his tongue. He was declared cancer-free in May 2002.

Since the 2004 tour, Van Halen had largely disappeared from the public eye, with the exception of occasional appearances including the 14th annual Elton John Academy Awards party and a performance at a Kenny Chesney concert. In December 2004, Van Halen attended "Dimebag" Darrell Abbott's funeral, and donated the black and yellow guitar featured on the Van Halen II album inlay, stating that it was always a favorite of Dimebag's. The guitar was put in Darrell's Kiss Kasket and he was buried with it.

On December 5, 2005, Van Halen's wife, Valerie Bertinelli, filed for divorce in Los Angeles Superior Court, after four years of separation, which was finalized on December 20, 2007. On March 8, 2007, Van Halen announced on the official band website that Van Halen was entering rehabilitation for unspecified reasons. However, both Sammy Hagar and Michael Anthony have made statements indicating that Van Halen's personality had changed due to alcohol abuse.

Van Halen emerged from rehabilitation and appeared publicly as an honorary official during the April 21, 2007, NASCAR event at Phoenix International Raceway. He unveiled a new Fender Stratocaster with a paint job made for the NASCAR races before the ceremony. In 2007, Van Halen was honored in the Xbox 360 version of Guitar Hero II.

On October 6, 2008, Van Halen proposed to his girlfriend, Janie Liszewski, an Actress and stunt-woman who became Van Halen's publicist in 2007. The two married on June 27, 2009, at his Studio City estate, with his son Wolfgang and Bertinelli in attendance. Eddie's brother Alex officiated the ceremony, while his son served as best man. On January 1, 2011, Eddie and Wolfgang Van Halen attended Bertinelli's remarriage.

In mid-January 2011, he attended the winter NAMM Show to present his new Wolfgang guitars, sharing the Fender booth with fellow guitar player Yngwie Malmsteen.

In August 2012, Van Halen underwent an emergency surgery for a severe bout of diverticulitis. His recovery time was four to six months, causing Van Halen to postpone their Japanese tour, which was originally scheduled to begin in November 2012.

Following Hagar's departure, the group briefly reunited with original singer David Lee Roth and released Best Of – Volume I, a greatest hits package, in October 1996. Two new songs were recorded for the album, "Me Wise Magic"—which reached No. 1 on the mainstream rock chart as a single—and "Can't Get This Stuff No More". However, previous disagreements resurfaced and the reunion did not last. Roth left in September 1996 after the MTV Video Music Awards.

Eddie has donated 75 of his personal guitars to The Mr. Holland's Opus Foundation stating: "I wanted to give back to the community, and especially kids in need who want an instrument but didn’t have the opportunity I had. I wanted to donate instruments because I have so many guitars and nobody would take them... until we found Mr. Holland’s Opus."