Natural products such as caffeine have been found to be effective in reducing body weight through lipolysis. Here, we report the successful loading of caffeine onto dissolving microneedle following inhibition of its crystal growth by hyaluronic acid (HA), the matrix material of the dissolving microneedle (DMN). Further, the anti-obesity activity of caffeine was evaluated in high-fat diet-induced obese C57BL/6J mice. After 6 weeks of caffeine loaded dissolving microneedle patch (CMP) administration, lipolysis improved significantly as shown by leptin and adiponectin activity, which resulted in considerable weight loss of about 12.8 ± 0.75% in high-fat diet-induced obese mice. Comparison of the levels of triglyceride, total cholesterol, high-density lipoprotein (HDL)-cholesterol, and low-density lipoprotein (LDL)-cholesterol after CMP administration with the initial levels in obese mice indicated significant anti-obesity activity of CMP. These findings suggested that a novel CMP with an increased amount of caffeine loaded onto DMN has therapeutic activity against obesity.