Obesity produces a systemic low-grade inflammation associated with many adverse health conditions and, as we recently learned, with complications of COVID-19. Functional studies in animal models have demonstrated that asperuloside, an iridoid glycoside found in many medicinal plants, has produced promising anti-obesity results. However, the safety profile and the anti-inflammatory properties of asperuloside remain unknown. Here, we confirmed the previously reported anti-obesity properties of asperuloside, and, importantly, we performed toxicity studies assessing cell viability providing a dose reference for future animal experiments. Asperuloside significantly reduced blood levels of leptin and the mRNA levels of orexigenic peptides, such as NPY and AgRP in mice consuming HFD, with no effect on mice eating a standard chow diet. In addition, our results indicate that ASP reduced both hypothalamic and hepatic mRNA levels of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α as well as the blood levels of plasminogen activator inhibitor-1 (PAI-1), which are known to play a major role in the development of insulin resistance and cardiovascular complications. Collectively, our findings suggest that asperuloside is a safe compound for long-term use in animal models and that it reduces the elevated levels of pro-inflammatory cytokines occurring in obesity.