Opuntia ficus-indica consumption improves obesity and glucose and lipid metabolism, to name a few; however, the involved mechanism is poorly understood and attributed primarily to fiber. Obesity was recently shown to increase microglial cell activation in the hypothalamus. Here, we hypothesized that the addition of cactus flour (CF) to a high-fat diet (HFD) reduces hypothalamic inflammation, which is a key regulator of energy balance metabolism. Adult male C57Bl/6j mice underwent HFD (60% cal from fat) exposure over 12 weeks to develop obesity. The same type of HFD added with CF (17%) was administrated for 4 weeks. Bodyweight and food intake were recorded during the treatment, and glucose and insulin tolerance were evaluated at the end of the treatment. Additionally, the behavioral satiety sequence (BSS) was performed, and adiposity, along with microglia activation and density in the arcuate nucleus was determined. Herein, we found that CF normalizes body weight and adiposity without changes in absolute food intake. Moreover, CF modulated the cumulative caloric intake in a diet-dependent manner. Feed efficiency was decreased; glucose tolerance and insulin sensitivity were improved with CF treatment. BSS showed a decreased resting time and increased grooming for animals with an HFD-CF. Finally, CF consumption normalized microglia density in the arcuate nucleus of the hypothalamus in obese mice and significantly decreased their activation. This study shed new light on the understanding of the effects of cactus to reduce body weight, adiposity and improve glucose metabolism, and suggest they are mediated by the reduction of the microglial activation of the hypothalamic arcuate nucleus.