The HK45 was developed as a product improvement of the highly regarded USP45, first released in the 1995. The Caliber .45 ACP HK45 includes several user-inspired enhancements including changeable grip panels (backstraps), a Picatinny MIL-STD-1913 accessory rail, better ergonomics, and more ambidextrous controls.

Along with the HK45 Compact, the HK45 was developed as a possible candidate for the Joint Combat Pistol (JCP) and Combat Pistol (CP) programs administered by the U.S. military in their search for a new service handgun to replace the 9-millimeter M9. These programs were suspended before completion and no pistols were selected.

The HK45 uses an HK proprietary O-ring barrel for precise barrel-to-slide lockup and optimal accuracy. HK45 barrels are made using the famous HK cold-hammer forging process for superior performance.