McDonald was born on June 20, 1953, in Gary, Indiana, and grew up in Chicago. He graduated from the U.S. Military Academy at West Point in 1975 with a Bachelor of Science degree in Engineering. At West Point he served as the Brigade Adjutant for the Corps of Cadets and was awarded the Silver Medal from the Royal Society for the Encouragement of Arts, Manufacturing and Commerce. After graduation, he served in the U.S. Army for five years, primarily in the 82nd Airborne Division, attaining the rank of Captain, and earned an MBA from the University of Utah in 1978. Upon leaving the military he received the Meritorious Service Medal.

McDonald joined Procter & Gamble in 1980. He served as a brand manager for Tide from 1984–1986. In 1989 he transferred to Toronto to lead P&G’s Canadian Laundry business, and moved to the Philippines as General Manager in 1991. In 1995 he became Vice President, Laundry & Cleaning Products Asia, and relocated to Japan. A year later in 1996, McDonald became President, Japan Operations, and in 1999, President, Northeast Asia. Two years later he moved to Brussels as President, Global Fabric Care and later President, Global Fabric & Home Care. He was appointed Vice Chairman, Global Operations in 2004 and appointed Chief Operating Officer in July 2007. McDonald became President and Chief Executive on July 1, 2009. He assumed the Chairman of the Board role January 1, 2010.

In 2007, McDonald received the inaugural Leadership Excellence Award from the U.S. Naval Academy and Harvard Business Review. He serves on the Board of Directors of Xerox, the McKinsey Advisory Council, and the Singapore International Advisory Council of the Economic Development Board.

During his tenure, investors criticized McDonald for being too loyal to P&G traditions, being too slow to pursue layoffs and other cuts, and being unable to produce new product innovations, particularly compared to his predecessor and replacement A.G. Lafley. He resigned from P&G on June 30, 2013, following pressure from the company board and activist investors such as Bill Ackman; he was replaced by his predecessor A.G. Lafley, who returned from retirement.

In 2014 McDonald led a community-based task force to help the city of Cincinnati renovate its Museum Center. As a result of this work, the Hamilton County Commissioners added a tax levy known as Issue 8 to the ballot in the fall of 2014 which passed, adding an additional sales tax to assist in paying for the renovations.

McDonald succeeded Eric Shinseki, who resigned on May 30, 2014, due to the Veterans Health Administration scandal of 2014.

On July 7, 2014, U.S. President Obama nominated McDonald to the Cabinet position of United States Secretary of Veterans Affairs.

One of McDonald’s first decisions in September 2014 was to increase salaries for physicians and dentists to close the pay gap with the private sector and to make VA an employer of choice. McDonald personally visited several medical schools to recruit new medical personnel in the early months of his tenure at VA. As of June 2015, VA had increased onboard staff by more 12,000 including over 1,000 physicians, 2,700 nurses, and 4,600 other select critical occupations.

On February 23, 2015, McDonald admitted he misspoke trying to engage a homeless veteran on January 30, 2015, about his serving in the U.S. Army Special Forces, a conversation that was recorded by a CBS television news crew accompanying him during a nationwide count of homeless veterans. “I have no excuse, I was not in the special forces” he told The Huffington Post, which first broke the story. The Huffington Post reported that “special operations forces” includes the Army Rangers and that McDonald “completed Army Ranger training and took courses in jungle, arctic and desert warfare. He qualified as a senior parachutist and airborne jumpmaster, and was assigned to the 82nd Airborne Division until he resigned his commission in 1980. While he earned a Ranger tab designating him as a graduate of Ranger School, he never served in a Ranger battalion or any other special operations unit.”

On May 23, 2016, Secretary McDonald stated that Disney does not measure wait times at its amusement parks, arguing that VA wait times are not an important measure. This statement was viewed as both insensitive to patients and incorrect, as Disney does measure wait times. He apologized the next day.

McDonald donated a statue of General Ulysses S. Grant that was unveiled on April 25, 2019 on The Plain at West Point.

In July 2020, McDonald was appointed by the George W. Bush Institute as the April and Jay Graham Fellow where he serves as a key member of the Military Service Initiative team. In September 2020, McDonald was selected by presidential nominee Joe Biden to be a member of his transition team’s advisory board.