Isaacson served as the president and CEO of the Aspen Institute from 2003 until 2018, when he announced that he would step down to become a professor of history at Tulane University and an advisory partner at the New York City financial services firm Perella Weinberg Partners. In November 2017, the Aspen Institute named Dan Porterfield, the president of Franklin and Marshall College, as Isaacson's successor.
In March 2017, Isaacson launched a podcast with Dell Technologies called Trailblazers, which focuses on technology's effects on business. In 2018, Isaacson was named as a cohost of "Amanpour & Company," a new show on PBS and CNN that replaced "The Charlie Rose Show."
His biography of Leonardo da Vinci was published on October 17, 2017, to positive reviews from critics. In August 2017, Paramount Pictures won a bidding war against Universal Pictures for the rights to adapt Isaacson's biography of da Vinci. The studio bought the rights under its deal with Leonardo DiCaprio's Appian Way Productions, which said that it planned to produce the film with DiCaprio as the star. Screenwriter John Logan (The Aviator, Gladiator) has been tapped to pen the script.