The 280 SL was introduced in December 1967 and continued in production through 23 February 1971, when the W 113 was replaced by the entirely new and substantially heavier R107 350 SL. Over the years, the W 113 evolved from a sports car into a comfortable grand tourer, and US models were by then usually equipped with the 4-speed automatic transmission and air conditioning. Manual transmission models came with the standard 4-speed or the optional ZF 5-speed, which was ordered only 882 times and thus is a highly sought-after original option today. In Europe, manual transmissions without air conditioning were still the predominant choice. Of the 23,885 280 SLs produced, more than half were sold in the US.

The main change was an upgrade to the 2,778 cc (2.8 L) M130 engine with 170 PS (125 kW; 168 hp) maximum power and 180 lb⋅ft (244 N⋅m) maximum torque, which finally gave the W 113 adequate power. The performance improvement was achieved by increasing bore by 4.5 mm (0.2 in), which stretched the limits of the M180 block, and required pairwise cylinder casts without cooling water passages. This mandated an oil-cooler, which was fitted vertically next to the radiator. Each engine was now bench-tested for two hours prior to being fitted, so their power specification was guaranteed at last.

North American models have a number of subtle differences, the most obvious one being the distinctive "sealed beam" bulb headlights required in the US versus the Bosch Lichteinheit headlights for the rest of the world. 1970 US models also acquired amber turn-signal lenses on the rear lights, later than most other countries. Other differences of the North American models include imperial gauges, chrome bumper guards, side reflectors (illuminated from 1970), lower rear-axle ratios for faster acceleration yet lower top speeds, and no "single-side" parking lights. US market 280 SL engines required emission control modifications, including "softer" valve timings, a reduced compression ratio and a modified injection pump, which reduced power from 170 PS (125 kW; 168 hp) to 160 PS (118 kW; 158 hp). In the US, automatic transmission, air conditioning, and white wall tires were much more popular than elsewhere.

European cars were popular as US gray-market imports: those vehicles were brought to the US some years after their original delivery in Europe. Early European imports had aftermarket hazard lights and Kangol seat belts fitted, US safety requirements that were adopted in Europe only in later production years.