Excess ultraviolet (UV) radiation causes numerous forms of skin damage. The aim of the present study was to assess and compare the photoprotective effects of cyanidin-3-O-glucoside (C3G) alone and encapsulated in chitosan nanoparticles (Nano-C3G) in a UVB-induced acute photodamage mouse model. Nano-C3G was developed from chitosan and sodium tripolyphosphate (TPP) by ionic gelation. The particle size, zeta potential, entrapment efficiency, drug loading, and in vitro release in 6 days were determined. Kunming (KM) mice were treated with Nano-C3G (125, 250, 500 μM) or C3G (500 μM) after part of the dorsal skin area was dehaired and then exposed to 2 J/cm of UVB. The nanocapsules were successfully produced and had a uniform and complete spherical shape without agglomeration. The size, zeta potential, entrapment efficiency, and drug loading of Nano-C3G was 288 nm, +30 mV, 44.90%, and 4.30%, respectively. C3G in the nanocapsules was released quite rapidly, and the release rate slowed down at higher pH. The animal experiment demonstrated that Nano-C3G could effectively reduce the UVB-induced lipid peroxidation, malondialdehyde, and 8-hydroxy-2′-deoxyguanosine contents; downregulate p53, Bcl-2-associated X (Bax), and caspase-3 and -9 expression; and balance the B-cell lymphoma-2/leukemia-2 ratio. Moreover, Nano-C3G (125, 250, 500 μM) improved the visual appearance, skin moisture, histologic appearance, and apoptotic index (based on TUNEL staining) under UVB exposure. In conclusion, these results suggest that Nano-C3G can reduce UVB-induced epidermal damage through the p53-mediated apoptosis signaling pathway. Moreover, Nano-C3G was more efficient than C3G at the same concentration (500 μM).