Al-Falih was born in 1960 in Dammam, Saudi Arabia, where he was also raised. He attended Texas A&M University, earning a bachelor's degree in mechanical engineering in 1982, and later pursued an MBA at the King Fahd University of Petroleum and Minerals, which he completed in 1991.

Al-Falih joined Saudi Aramco (formerly, Aramco) in 1979. For over several years, he held positions of increasing responsibility and in 1992, he joined the Consulting Services Department (CSD). He supervised several technical units, mainly the Mechanical and Civil Systems Division and was named manager of CSD in January 1995. He was assigned as manager, Ras Tanura Refinery Maintenance Department in late 1995; and by 1998; manager, Business Analysis Department.

In July 1999, Al-Falih became President of Petron Corporation, a joint venture between Saudi Aramco and the Philippine National Oil Company. He returned to the Kingdom in September 2000 to serve as vice chairman on the Saudi Aramco Study Team for Upstream Gas Ventures, until his appointment as vice President of Gas Ventures Development and Coordination in May 2001. He played an instrumental role in the negotiations with the international oil companies (IOCs) & other major national oil companies (NOCs) in connection with the Kingdom's Natural Gas Initiative. Ultimately, four joint ventures, namely - South Rub' al-Khali Company (SRAK), Luksar Energy, Sino Saudi Gas & EniRepSa Gas were consummated between Saudi Aramco and various leading IOCs, Nocs and emerging oil companies.

In October 2004, Al-Falih was appointed to the Board of Directors of Saudi Aramco. He also served as chairman of the board of the South Rub' al-Khali joint venture between Shell, Total and Saudi Aramco.

In Nov 2008, Abdallah S. Jum'ah, then President and CEO of Saudi Aramco, retired and Khalid A. Al-Falih, who was serving as Aramco's executive vice President of operations, was appointed as the new President and CEO of the company, effective January 1, 2009.

The global oil economy caused prices to fluctuate dramatically, from a peak of almost $108 in June 2014 to $26 per barrel in February 2016, the lowest point since 2003. In May 2016, Al-Falih was appointed Minister of Energy, Industry and Mineral Resources, replacing outgoing Ali al-Naimi. The national plan Vision 2030 announced in April 2016 is designed to reduce the Kingdom’s dependence on oil revenue, a new direction which affected the makeup of Saudi ministries. In the royal decree announcing the appointment of Al-Falih, the former Petroleum Ministry was renamed "Ministry of Energy, Industry and Mineral Resources," incorporating also the Ministry of Electricity. Al-Falih also holds the position of chairman of the Board of Directors of Aramco, whose CEO is Amin H. Nasser.

The oil crash caused OPEC countries to react by diminishing production, the organization’s first cut in eight years. Minister Al-Falih urged fellow OPEC member countries to stop exceeding their output targets, and met with Venezuelan and Kazakh counterparts in August 2017 in order to extend the deal of cutting production until March 2018, by at least three more months.