The avermectin derivative doramectin is widely used clinically as an antiparasitic drug and, in addition, doramectin may have a modulatory role in obesity. Adipose tissue macrophage recruitment and polarization play an important role in obesity-induced inflammation and insulin resistance. The aim of this study was to investigate the effects of doramectin on high-fat diet-induced inflammation and macrophage polarization in white adipose tissue of epididymis of obese mice. We found that compared with high-fat diet-fed obese mice, doramectin treatment resulted in a significant decrease in body weight and lipid levels, improved insulin resistance, an increase in the proportion of M2-type macrophages and a decrease in the proportion of M1-type macrophages in the epididymal white adipose tissues, as well as a decrease in the infiltration of inflammatory cells in the adipose tissues. Thus, doramectin can ameliorate high-fat diet-induced obesity and adipose inflammation by affecting macrophage polarization in white adipose tissue.