This study aimed to develop a curcumin-loaded bilosomal hydrogel for topical wound healing, addressing curcumin's poor aqueous solubility and low oral bioavailability. Bilosomes were fabricated using the thin film hydration technique with cholesterol, Span 60, and bile salts (sodium deoxycholate or sodium cholate). The optimal bilosomal formulation contained cholesterol/Span 60 (1:10 w/w) and 5 mg of sodium deoxycholate, yielding a particle size of 246.25 ± 11.85 nm, PDI of 0.339 ± 0.030, ZP of -36.75 ± 0.14 mV, and 93.32% entrapment efficiency. This bilosomal formulation was then incorporated into an alginate dialdehyde/chitosan hydrogel cross-linked with calcium chloride. The hydrogel demonstrated high water uptake (729.50 ± 43.13%) and sustained drug release over five days. In vivo studies on male Albino rats showed that the curcumin-loaded bilosomal hydrogel promoted complete wound closure within three weeks, with improved healing mechanisms compared to curcumin dispersion and plain hydrogel. The hydrogel exhibited robust, efficient, and user-friendly properties for wound healing. Key findings include the hydrogel's high water uptake, sustained drug release, and enhanced wound healing efficacy. The study highlights the potential of curcumin-loaded bilosomal hydrogel as a novel, bioactive, biodegradable, and biocompatible wound treatment.This study aimed to develop a curcumin-loaded bilosomal hydrogel for topical wound healing, addressing curcumin's poor aqueous solubility and low oral bioavailability. Bilosomes were fabricated using the thin film hydration technique with cholesterol, Span 60, and bile salts (sodium deoxycholate or sodium cholate). The optimal bilosomal formulation contained cholesterol/Span 60 (1:10 w/w) and 5 mg of sodium deoxycholate, yielding a particle size of 246.25 ± 11.85 nm, PDI of 0.339 ± 0.030, ZP of -36.75 ± 0.14 mV, and 93.32% entrapment efficiency. This bilosomal formulation was then incorporated into an alginate dialdehyde/chitosan hydrogel cross-linked with calcium chloride. The hydrogel demonstrated high water uptake (729.50 ± 43.13%) and sustained drug release over five days. In vivo studies on male Albino rats showed that the curcumin-loaded bilosomal hydrogel promoted complete wound closure within three weeks, with improved healing mechanisms compared to curcumin dispersion and plain hydrogel. The hydrogel exhibited robust, efficient, and user-friendly properties for wound healing. Key findings include the hydrogel's high water uptake, sustained drug release, and enhanced wound healing efficacy. The study highlights the potential of curcumin-loaded bilosomal hydrogel as a novel, bioactive, biodegradable, and biocompatible wound treatment.