After graduating from UCLA Law, Lowell joined the law firm of Irell & Manella in the fall of 1973 as an associate and specialized in Business and tax law in the Los Angeles-based office.

In 1979, he joined Drexel Burnham Lambert’s High Yield and Convertible Bond Department, also known as the “junk bond” department. He served as a departmental senior vice President until he resigned in 1989. His duties were reported to be “mostly administrative,” but he also provided financial analysis of companies. He was not a registered representative with any securities exchange.

Lowell Milken established the Lowell Milken Family Foundation in 1986 to support and provide funding for organizations and initiatives that strengthen communities through education and lifelong learning.

First presented by Lowell Milken in 1987, the Milken Educator Awards program works with state departments of education to identify teachers, principals and education specialists who are improving student achievement, making significant contributions to a school's level of excellence and elevating the teaching profession. In 2017-18, 45 new honorees will join the National Milken Educator Network, a group of over 2,700 outstanding eductors who have received the Milken Educator Award.

In March 1989, after a long investigation of Lowell’s brother Michael Milken, the government issued a 98-count indictment of Michael Milken, who was charged with racketeering and a "long list of mail, wire and securities frauds." The indictment also named Lowell in two charges of racketeering and 11 counts of fraud. Michael Milken, in a plea bargain deal, pleaded guilty and went to prison. As part of that deal, the government dropped charges against Lowell Milken, but in March 1991, he was barred from working in the securities industry as part of a settlement with the Securities and Exchange Commission.

In 1990, Lowell Milken founded the Milken Archive of Jewish Music, a project to preserve music of the American Jewish experience.

After years in the planning stages, in 1996, Lowell co-founded Knowledge Universe with Michael Milken and Larry Ellison. In 2003, they became the sole owners of the company. In the United States, Knowledge Universe is the largest early childhood education company and operates under the KinderCare Learning Centers, Knowledge Beginnings, CCLC, The Grove School, Champions and Cambridge Schools brands. Internationally, it oversees early childhood education, K-12 education and post-secondary education programs and is headquartered in Singapore. Lowell continues to serve as vice chairman of Knowledge Universe Education and he is Chairman of Knowledge Universe Education Holdings Inc.

In 1999, Lowell Milken founded the TAP System for Teacher and Student Advancement, a comprehensive school reform currently impacting more than 250,000 educators and 2.5 million students across the country . The system is based on four integrated and aligned elements: Multiple careers paths, continuous school-based professional development, instructionally-focused Teacher evaluation, and performance-based compensation for educators. In 2005, Lowell founded an independent public charity to support and manage the TAP System, The National Institute for Excellence in Teaching (NIET), and has since served as its Chairman.

Over the past three decades, Lowell Milken has founded additional nonprofit organizations, including the Lowell Milken Family Foundation and the Lowell Milken Center. In 2000, he was named one of America’s most generous Philanthropists by Worth Magazine.

The Lowell Milken Center was established by Lowell Milken in 2007 in partnership with Kansas Milken Educator Norman Conard. The public nonprofit organization discovers, develops and communicates the stories of unsung heroes who have made a profound and positive difference on the course of history and includes a 6,000-square-foot museum space with permanent and rotating exhibitions.

The Lowell Milken Institute for Business Law and Policy was founded at UCLA School of Law in 2011.

The Education Commission of the States (ECS) honored Lowell Milken as the 2017 recipient of the James Bryant Conant Award on June 29, 2017. The award is named for the co-founder of Education Commission of the States and former President of Harvard University, and recognizes outstanding individual contributions to American education. In May 2015, Lowell Milken accepted an honorary Doctorate of Humane Letters from Chapman University’s George L. Argyros School of Business and Economics. Lowell was honored as UCLA Law 2009 Alumnus of the year for his accomplishments in public and community Service, particularly in the area of education and school reform. In 2009, Hebrew Union College presented Lowell with a Doctor of Humane Letters, honoris causa, in Los Angeles. In 2004, Lowell was honored by the Jewish Theological Seminary of America during the event "Only in America: Jewish Music in a Land of Freedom." In 2000, Lowell Milken was named one of America’s most generous Philanthropists by Worth Magazine. Lowell Milken's work in Business and philanthropy has been recognized by the National Association of State Boards of Education, the Horace Mann League and the National Association of Secondary School Principals.