In the flotation system of copper-nickel sulfide ores, fine-grained vein minerals, mainly serpentine, are very susceptible to be entrained into the concentrate with the froth, resulting in negative impacts on the concentrate product and the subsequent smelting process. In order to understand the influencing factors and whether there was any interaction in the process of froth entrainment of fine-grained serpentine and other vein minerals in the flotation system of copper-nickel sulfide ores, a response surface analysis (RSA) test was carried out on the basis of a one-factor test, and the effects of the interaction of the three factors, namely, foam agent dosage, gas volume velocity, and the foam layer thickness, were analyzed to determine the effects of the mechanical entrainment. The results of flotation entrainment showed that the foam agent dosage and pulp concentration affected the mechanical entrainment recovery of serpentine by influencing the water recovery and entrainment degree, while the gas volume velocity, particle size, and thickness of the foam layer only affected the entrainment degree and thus the recovery. The response surface test predictions were basically the same as the actual values, indicating that the predictions of the regression model were more accurate and can be used to analyze and predict the test results. The effects of the three factors investigated on the mechanical entrapment recovery of serpentine were foam agent dosage>foam layer thickness>gas volume velocity. Foaming agent dosage and foam layer thickness had significant influence on the mechanical entrainment of serpentine, which was a significant influence factor. The response surface method generally optimized the flotation conditions for the useful minerals rather than the vein minerals, and the interaction analysis showed that the different factors did not interact with each other on the mechanical entrainment of serpentine.