Lee Eisenberg joined Esquire right out of graduate school and was appointed editor-in-chief several years later. He then spent the better part of the next two decades at the magazine, during which time he worked with a wide range of distinguished journalists and literary figures—Nora Ephron, Truman Capote, Richard Ford, Tom Wolfe, among many others. He was also the founding editor of Esquire in the UK.

In 1991, Eisenberg was recruited to be one of six original partners of the Edison Project, an initiative to design a business and academic plan for a proposed system of world-class schools. In 1995, he joined Time Inc. where, as a consulting editor, he helped Time magazine launch a series of new initiatives, including Time.com; Time for Kids; and The Time 100, a collaboration with CBS News that chronicled the most influential men and women of the 20th century.

In 2004, he began work on The Number: A Completely Different Way to Think About the Rest of Your Life. The book, which was published two years later, earned a place on numerous national bestseller lists, including the New York Times, The Wall Street Journal, Businessweek, and USA Today, and was published internationally. Businessweek named it one of the top-ten financial books of the year. The Number also  gave rise to a public-speaking career in the U.S. and abroad, which is ongoing. 

Eisenberg is also the author of Shoptimism: Why the American Consumer Will Keep on Buying No Matter What, which was published in 2009 by Free Press/Simon & Schuster. It has been cited for its insights into both the marketing and customer sides of American consumerism. 

His newest book, The Point Is: Making Sense of Birth, Death, and Everything in Between, is published by Twelve, an imprint of the Hachette Book Group. 

Eisenberg has also been chief creative and marketing officer at two publicly held companies, where he led a broad range of initiatives. 

He has been a visiting scholar at the University of Pennsylvania, a scholar in residence at the Newberry Library in Chicago, and was one of the founding fathers of Rotisserie League Baseball, the forerunner of fantasy sports. He no longer plays golf, though he wrote a book about why he did:  Breaking Eighty: A Journey Through the Nine Fairways of Hell. .