Background: Obesity spurred by a high-fat diet (HFD) has emerged as a significant worldwide health issue. Caffeic acid (CA) is a plant-derived phenolic compound found in various foods such as coffee, wine, and tea. It exhibits antioxidant, anti-inflammatory, and anticarcinogenic properties. However, the therapeutic potential of this substance is hindered by its poor water solubility and low oral bioavailability. Aim: In this study, CA was loaded into liposomes Caffeic Acid -Loaded Liposomes (CA-Lip) , and the potential role of CA-Lip in mitigating HFD-induced obesity in rats was examined. Methods: Forty male Wistar rats were used in this investigation. They were allocated into four groups: the first was fed a regular diet; the second received a normal diet plus CA-Lip; the third received an HFD; and the fourth received both an HFD and CA-Lip. Results: The developed CA-Lip showed a particle size of 125 nm, zeta potential of -15 mV, and entrapment efficiency of 82%. The HFD+CA-Lip group's body weight was considerably lower than that of the HFD group. The HFD+CA-Lip group also showed a significant improvement in their serum lipid profiles. CA-Lip lowered levels of adipokines, which encourage inflammation, including leptin, interleukin-6, and tumor necrosis factor-α. It also reduced the size of the adipocytes when compared to the HFD control group. Furthermore, it reversed the HFD-induced upregulation of Hh genes [protein patched homolog 1 (PTCH1), Hh-interacting protein (HHIP), glioma-associated oncogene homolog 1 (Gli1), and smoothened (Smo) receptor] in adipose tissue. Conclusion: In summary, CA-Lip may reduce obesity and related inflammation by activating the Hh signaling pathway.