Natural polyphenols, such as resveratrol (RES) or epicatechin (EPI), are attractive for treatments of various diseases, including vaginal infections and inflammation, because of their strong anti-oxidative and anti-inflammatory properties. However, their low solubility and consequent poor bioavailability limit their therapeutic uses. To overcome these limitations, a vaginal delivery system comprising either RES or EPI liposomes-in-hydrogel was developed. This system permits therapeutic action of both liposomal polyphenol (RES or EPI) and chitosan-based hydrogel. Liposomes of around 200 nm and entrapment efficiency of 81% and 77% for RES and EPI, respectively, were incorporated into chitosan hydrogel, respectively. Medium molecular weight chitosan (2.5%, w/w) was found to have optimal texture properties and mucoadhesiveness in ex vivo conditions. The in vitro release studies confirmed the sustained release of polyphenols from the system. Both liposomal polyphenols and polyphenols-in-liposomes-in-hydrogel exhibited only minor effects on cell toxicity. EPI showed superior radical scavenging activity at lower concentrations compared to antioxidants vitamin C and E. Anti-inflammatory activity expressed as the inhibitory activity of formulations on the NO production in the LPS-induced macrophages (RAW 264.7) confirmed the superiority of EPI liposomes-in-hydrogel. The plain liposomes-in-hydrogel also exhibited potent anti-inflammatory activity, suggesting that chitosan hydrogel acts in synergy regarding anti-inflammatory effect of formulation.