He later worked at America West Airlines, before becoming the chief restructuring officer of GMAC, LLC.

Isom then returned to America West, which had in 2005 merged with and was now named US Airways, to become Executive Vice President and COO.

[7] Prior to officially becoming CEO, on March 17, 2022, it was announced by United States Secretary of Homeland Security Alejandro Mayorkas that Isom had been named to the Homeland Security Advisory Council.

[8] On January 29, 2025, Isom released a video statement following the Potomac River mid-air collision involving American Eagle Flight 5342.

[9] Isom has donated to both Democratic and Republican political campaigns as well as to the American Airlines PAC.