The effect of microwave treatment on the grinding and flotation performance of a typical copper–nickel sulfide ore was evaluated, based on the determination of its microwave absorption capability, grinding and flotation indexes such as crack percentage, mineral liberation degree, particle size distribution, relative work index (RWI), metal enrichment ratio and recovery. There were obvious differences between the microwave absorption capabilities of the main minerals in the ore, as demonstrated by their different microwave penetration depths. They also induced temperature differences between sulfide minerals and gangue minerals which could reach 418 °C after microwave treatment for 20 s. It was shown that microwave treatment could effectively improve the grindability of the ore, as proven by the increase in fine particles smaller than 0.074 mm and the decrease in RWI after grinding due to the higher crack percentage and mineral liberation degree. Moreover, microwave treatment affected the ore floatability because of the generation of cuprite, retgersite, and rozenite with poor floatability when the treatment time was extended. By microwave treatment for a proper time, 20 s, an optimal balance between the grindability and flotation performance could be achieved. Compared with the untreated ore, the RWI of the ore decreased by 11.5%. After flotation, the Cu and Ni enrichment ratios of the flotation concentrate increased by 0.3 and 0.2, respectively. Meanwhile, their corresponding recoveries increased by 4.2% and 3.1%. This study provides new insights for the treatment of copper–nickel sulfide ore to enhance the grinding and flotation process.