Considered the most effective variant, the Model 52 was developed to face the powerful American F6F Hellcat and F4U Corsair, superior mostly for engine power and armament. The variant was a modest update of the A6M3 Model 22, with non-folding wing tips and thicker wing skinning to permit faster diving speeds, plus an improved exhaust system. The latter used four ejector exhaust stacks, providing an increment of thrust, projecting along each side of the forward fuselage. The new exhaust system required modified "notched" cowl flaps and small rectangular plates which were riveted to the fuselage, just aft of the exhausts. Two smaller exhaust stacks exited via small cowling flaps immediately forward of and just below each of the wing leading edges. The improved roll-rate of the clipped-wing A6M3 was now built in.
- "A6M5a Model 52a «Kou»," featuring Type 99-II cannon with belt feed of the Mk 4 instead of drum feed Mk 3 (100 rpg), permitting a bigger ammunition supply (125 rpg)
- "A6M5b Model 52b «Otsu»," with an armor glass windscreen, a fuel tank fire extinguisher and the 7.7 mm (.303 in) Type 97 gun (750 m/s muzzle velocity and 600 m/1,970 ft range) in the left forward fuselage was replaced by a 13.2 mm/.51 in Type 3 Browning-derived gun (790 m/s muzzle velocity and 900 m/2,950 ft range) with 240 rounds. The larger weapon required an enlarged cowling opening, creating a distinctive asymmetric appearance to the top of the cowling.
- "A6M5c Model 52c «Hei»" with thicker armored glass in the cabin's windshield (5.5 cm/2.2 in) and armor plate behind the pilot's seat. The wing skinning was further thickened in localized areas to allow for a further increase in dive speed. This version also had a modified armament fit of three 13.2 mm (.51 in) guns (one in the forward fuselage, and one in each wing with a rate of fire of 800 rpm), twin 20 mm Type 99-II guns and an additional fuel tank with a capacity of 367 L (97 US gal), often replaced by a 250 kg bomb.
The A6M5 had a maximum speed of 540 km/h (340 mph) and reached a height of 8,000 m (26,250 ft) in nine minutes, 57 seconds. Other variants were the night fighter A6M5d-S (modified for night combat, armed with one 20 mm Type 99 cannon, inclined back to the pilot's cockpit) and A6M5-K "Zero-Reisen"(model l22) tandem trainer version, also manufactured by Mitsubishi.