Samueli attended UCLA, where he received his bachelor's degree (1975), master's degree (1976), and Ph.D (1980), all in the field of electrical engineering. His Ph.D. advisor was Alan N. Willson Jr. and his Ph.D. dissertation is entitled "Nonperiodic forced overflow oscillations in digital filters".

In 1991, while still working as a professor at UCLA, Samueli co-founded Broadcom with one of his Ph.D. students, Henry Nicholas. Each invested $5,000 and initially worked out of Nicholas' Redondo Beach home. They rented their first office in 1992 in Westwood, CA near the UCLA campus and moved to Irvine, CA in 1995 at which time Samueli took a leave of absence from UCLA to be at Broadcom full-time. Broadcom went public three years after that. Samueli still remains on leave from UCLA and he continues to be listed on the Electrical and Computer Engineering Department faculty roster.

After Broadcom went public in 1998 the Samueli Foundation was created. The foundation focuses its giving in the areas of education, health, youth services, and Jewish culture and values. In 2012 the Samueli's joined the Giving Pledge, initiated by Warren Buffett and bill and Melinda Gates, whose members pledge the majority of their wealth to philanthropy.

Given Henry Samueli's background in engineering and education, some of their earliest philanthropic gifts were in these areas. In 1999 the Samueli's made major donations to the UCLA School of Engineering and Applied Science and the UC Irvine School of Engineering, both of which have since been named after him.

During the Technology boom in the 2000s, Samueli and Broadcom co-founder Henry T. Nicholas III awarded millions of stock options to attract and reward employees. Prosecutors alleged Samueli and Nicholas granted options to others, including some other top executives, but not themselves, to avoid having to report $2.2 billion in compensation costs to shareholders. In 2006 both the Securities and Exchange Commission and the Department of Justice began investigating Broadcom Corporation for backdating of stock options.

A major passion of Susan Samueli is in the areas of complementary and alternative Medicine and integrative health and wellness. In 2001 the Samueli's established the Susan Samueli Center for Integrative Medicine at UC Irvine. They have also supported the research of the John Wayne Cancer Institute in Santa Monica, California, in cancer prevention and treatment. In 2017 the Samueli's made a transformational $200 million gift to UC Irvine to create the Susan and Henry Samueli College of Health Sciences, a first-of-its-kind College of Health Sciences focused on interdisciplinary integrative health. As part of the gift, the existing Susan Samueli Center for Integrative Medicine was elevated to become the Susan Samueli Integrative Health Institute.

In 2003 the Samueli's purchased the management contract for the Arrowhead Pond of Anaheim Sports and entertainment venue, creating Anaheim Arena Management, LLC, to oversee all operations of the arena, and in 2005 they purchased the Mighty Ducks of Anaheim National Hockey League (NHL) club, the arena's largest tenant, from the Walt Disney Company for $75 million. In 2006, the Samueli's announced the team's name change to the Anaheim Ducks and the arena's name change to Honda Center. In 2007 the Anaheim Ducks became the first California team ever to win the Stanley Cup championship.

On September 8, 2008, U.S. District Court Judge Cormac Carney rejected the plea deal that called for Samueli to receive probation, writing: "The court cannot accept a plea agreement that gives the impression that justice is for sale".

16 months later, on December 10, 2009, Judge Carney, after hearing the testimony of all the witnesses at the trial of CFO william Ruehle, dismissed the case against Samueli (as well as Ruehle and Nicholas), citing Samueli's testimony as well as prosecutorial misconduct. In his ruling Judge Carney stated "The uncontroverted evidence at trial established that Dr. Samueli was a brilliant Engineer and a man of incredible integrity. There was no evidence at trial to suggest that Dr. Samueli did anything wrong, let alone Criminal. Yet, the government embarked on a campaign of intimidation and other misconduct to embarrass him and bring him down." He further added in his ruling "Needless to say, the government’s treatment of Dr. Samueli was shameful and contrary to American values of decency and justice." The judge ordered Dr. Samueli's plea agreement to be "expunged" from his record and stated "Dr. Samueli now has a clean slate."

He is a named Inventor in 75 U.S. patents. He is a Fellow of the Institute of Electrical and Electronics Engineers (IEEE), a Fellow of the American Academy of Arts and Sciences (AAAS) and a Member of the National Academy of Engineering (NAE). In 2012 Samueli won the Marconi Prize and Fellowship for "pioneering advances in the development and commercialization of analog and mixed signal circuits for modern communication systems, in particular the cable modem.

In 2015, Samueli received a prize from the Israeli government for his global contribution to innovation and his contribution to innovation in Israel, at the "Innovex" conference for innovation in Technology.

As of December 2016, Samueli serves on the Executive Committee of the NHL Board of Governors.

In 2017 Forbes reported the Anaheim Ducks were worth $415 million.

As of February 2018, Forbes estimates Samueli's net worth at $3.8 billion.