In 1959, Malone graduated from Hopkins School in New Haven, Connecticut. In 1963, he graduated from Yale University with a bachelor's degree in electrical engineering and economics, where he was a Phi Beta Kappa and National Merit scholar. In 1964, Malone graduated from Johns Hopkins University with a master's degree in industrial management. He received a master's in electrical engineering at an NYU program at Bell Labs in 1965 before receiving his PhD in operations research at Johns Hopkins in 1967.
In 1963, Malone began his Business career at Bell Telephone Laboratories of AT&T, working in economic planning and research and development. In 1968, he joined McKinsey & Company, and in 1970, became group vice President at General Instrument Corporation (GI). He was later President of Jerrold Electronics, a GI subsidiary. For twenty-four years, from 1973 to 1996, Malone served as President and CEO of Tele-Communications Inc. (TCI).
In 1994, Wired portrayed Malone on their cover as "Mad Max" from The Road Warrior (also known as Mad Max 2), with an interview describing his battles with the FCC. He is also known as the "Cable Cowboy".
Malone reportedly shuns the limelight and glamorous lifestyle and takes his family vacations alongside long time friend Gary Biskup, in a recreational vehicle. However, in Business dealings he has been dubbed "Darth Vader", a nickname allegedly given to him by Al Gore when Malone was the head of TCI, where he demanded equity positions in cable programming services in return for carriage, and attempted to defeat the must-carry rules which protected broadcasters, a battle which the cable industry eventually lost in 1997 in the U.S. Supreme Court. In a news article published in The Denver Post newspaper in 2017, it was disclosed that Malone received the "Darth Vader" title because Al Gore's grandmother lived in territory where TCI provided Service. She didn't understand why cable bills went up when the company was delivering more content.
In 2000, Malone gave $24 million for the construction of Yale's Daniel L. Malone Engineering Center, named in honor of his Father. In 2011, Malone gave the Johns Hopkins Whiting School of Engineering's largest gift ever of $30 million for a new building on Homewood Campus. The building will be named Malone Hall. In the same year, he gave the Yale School of Engineering & Applied Science's largest gift ever of $50 million. Malone has also given $60 million to Hopkins School to fund the construction of two new buildings, Malone Science Center, named for his Father, as well as Heath Commons, named after his favorite Hopkins Teacher.
Malone is on the boards of Directors for Bank of New York Mellon, the Cato Institute, and Expedia.com. Malone is chairman emeritus of Cable Television Laboratories, Inc. and chairman of Liberty Global, Inc., and formerly the DirecTV Group. His rise to chairman at Liberty Global was contentious at times. In 2005, Malone held 32 percent of the shares in the media company News Corporation, and although only about half were voting shares, Rupert Murdoch reportedly had concerns that he might lose control of his company to Malone, and tried to oust him from the firm with a "poison pill" strategy. He was Director of the National Cable & Telecommunications Association (NCTA) from 1974 to 1977, and again from 1980 to 1993. During the 1977–1978 term, Malone was the NCTA's treasurer.
Malone owns Silver Spur Ranches, a ranching and beef company which includes the Silver Spur Ranch in Encampment, Wyoming, Bell Ranch and the TO Ranch in New Mexico as well as ranches in Walden, Colorado and Kiowa, Colorado. As of 1 February 2011, he has surpassed Ted Turner as the largest individual private landowner in the US, owning 2,100,000 acres (8,500 km) of land, most of which is in Maine. His international real estate holdings include Humewood Castle and Castlemartin House and Estate, both in Ireland.
In 2014, Malone and his wife donated $42.5 million to Colorado State University to help create their Institute for Biologic Translational Therapies, which aims to develop stem cell and other treatments for animals and people. Of the donation, $32.5 million will pay for half the construction costs and $10 million will go to operational expenses.
His political beliefs have been described as libertarian. He donated US$ 250,000 to Donald Trump's inauguration in 2017, with colleague Greg Maffei, Liberty Media, and Liberty Interactive each donating a further US$ 250,000.