Two YF-12s were flown in a joint Air Force-NASA research program at the NASA Flight Research Center (after 1976, the NASA Dryden Flight Research Center) between 1969 and 1979. A third shared plane, piloted primarily by the Air Force, was lost to an in-flight fire in 1971.

With the YF-12, NASA researchers hoped to establish a technology base for the design of an efficient propulsion system for supersonic cruise aircraft, such as a Supersonic Transport (SST). Primary areas under investigation included inlet design analysis, propulsion system steady-state and dynamic performance, inlet engine control systems, and airframe/propulsion interactions. 

To measure the thermal loads on the YF-12 required some extraordinary ground tests. At the supersonic speeds the aircraft achieved, high temperatures produced by friction with the atmosphere made it difficult to separate the aerodynamic from the purely thermal effects upon the airplane.

In something of a departure for Blackbird researchers, NASA and Lockheed engineers investigated space shuttle landing dynamics using the YF-12C. Several flights, conducted in April and June 1973, demonstrated shuttle-type flight characteristics during low lift-to-drag approaches. 

Because air friction subjected the plane to extreme heat during flight, the YF-12 was also used to study high-temperature phenomena unrelated to the plane itself. Perhaps the most significant of these studies was the Cold Wall Experiment, which involved exposing a cooled cylinder to the friction and heat of a Mach 3 environment.