The 645 series engines entered production in 1965. As the 567 series had reached its limits in horsepower increases, a larger displacement was needed; this was accomplished by increasing the bore from 8+1⁄2 in (216 mm) on the 567 series to 9+1⁄16 in (230 mm) on the 645 series, while maintaining the same stroke and deck height. While the crankcase was modified from the 567 series, 567C and later engines (or 567 engines which have been modified to 567C specifications, sometimes referred to as 567AC or 567BC engines) can accept 645 series service parts, such as power assemblies. Conversely, the 567E engine employs a 645E series block with 567 series power assemblies.

All 645 engines utilize either a Roots blower or a turbocharger for cylinder scavenging. For turbocharged engines, the turbocharger is gear-driven and has an overrunning clutch that allows it to act as a centrifugal blower at low engine speeds (when exhaust gas flow and temperature alone are insufficient to drive the turbine) and a purely exhaust-driven turbocharger at higher speeds. The turbocharger can revert to acting as a supercharger during demands for large increases in engine output power. While more expensive to maintain than Roots blowers, EMD claims that this design allows "significantly" reduced fuel consumption and emissions, improved high-altitude performance, and even up to a 50 percent increase in maximum rated horsepower over Roots-blown engines for the same engine displacement.