Ghrelin is a stomach-derived peptide that acts as an orexigenic hormone in the hypothalamus stimulating food intake through the growth hormone secretagogue receptor (GHS-R1a). Dysregulated ghrelin signalling may contribute to the development of metabolic disorders such as obesity. Current pharmacologic anti-obesity treatments lack efficacy and have shown severe side effects, highlighting the urgent need for novel strategies contributing to the maintenance of a healthy weight. Natural products are receiving special consideration as sources of bioactives with potential beneficial health effects which may be safer and more attractive for consumers than synthetic therapeutics. One example is the plant extract derived from the dried tuberous roots of Harpagophytum procumbens which has been used traditionally as herbal medicine for a variety of conditions, and currently is mainly used as an anti-inflammatory agent and as an analgesic. In addition, it has some folkloric precedent as a modulator of appetite. This study aims to investigate the effect of H. procumbens on GHS-R1a receptor modulation in vitro and analyse its effects on food intake in vivo. GHS-R1a receptor activating potential of H. procumbens soluble extract was analysed by calcium mobilization and receptor internalization assays in human embryonic kidney cells (Hek) stably expressing the GHS-R1a receptor. Furthermore, cumulative food intake was investigated in male C57Bl/6 mice following intraperitoneal (IP) administration of the soluble H. procumbens extract. Exposure to H. procumbens extract demonstrated a significant increased cellular calcium influx but did not induce subsequent GHS-R1a receptor internalization, which is characteristic of full receptor activation. A significant anorexigenic effect was observed in male C57BL/6 mice following peripheral administration of H. procumbens extract. We conclude that H. procumbens root extract is a potential novel source of potent anti-obesity bioactives. These results reinforce the promising potential of natural bioactives to be developed into functional foods with weight-loss and weight maintenance benefits.