The Santa Fe was the first and largest purchaser of EMD's SD45-2 acquiring ninety 20-cylinder turbo-charged 645 3600-hp engine’d SD45-2s in three orders between May 1972 and May 1974. Introduced with the other EMD 'Dash 2' models in 1972, the SD45-2 had improved electrical systems, higher capacity D77 traction motors, 4000 gallon fuel tank, and a redesigned HT-C truck. The SD45-2 addressed the radiator problem of the SD45 by replacing the three section angular mounting with a longer radiator area, almost four feet longer than the SD45, divided into two sections with three widely-spaced fans. The SD45-2 was mounted on the same frame (68' 10") as the SD40-2 with the cab centered over the middle axle but lacked the long end platform. The SD45-2s were initially assigned to the Chicago/Kansas City/West Coast freight pool running on some of Santa Fe's hottest trains on the mainline. SD45-2s 5687-5704 from the second order were high-speed locomotives (59:18 gearing - 90 mph maximum speed) purchased for use on the high-priority premium service COFC/TOFC trains 198/891 Super C.
 
          The most notable SD45-2s were the Bicentennial units 5700-5704 painted red/white/blue between 1975 and 1978, with five-foot U.S. Presidential seals bolted-on, to honor the Nation's 200th Birthday. The Santa Fe went all out for the Bicentennial doing the most repainting of any Class I road with these five consecutively numbered SD45-2s, and assigned them to the Super C where one could usually be found on the point position leading this premium service.

Athearn Genesis SD-45-2 with the following details added:

• Removed MRC decoder and incandescent bulbs, replaced with Tsunami, Keep Alive, and LED lights
• LED ground lights under cab
• Details West speedometer SR-364
• Details West mirrors RM-353
• Athearn Genesis windshield wipers
• Painted control stand and crew figures