Dendrobium officinale protocorms (DOPs) are a specific developmental stage of Dendrobium officinale KIMURA et MIGO, which is used in folk medicine to ease skin issues, such as wrinkles and erythema. The purpose of the current study was to evaluate the effect of DOPs on UV irradiation-induced skin damage in bc_nu hairless mice, using matrixyl as a positive control. Hairless mice were randomly separated into 6 groups (8 mice per group). The normal control group received solvent and was not exposed to UV irradiation, while the model control group received solvent and was exposed to UV irradiation. The positive control group was subjected to UV irradiation and then received a 10 mg/mL formulation of matrixyl. The DOPs-treated groups received a transdermal application of a DOPs formulation after 4 weeks of UV irradiation. Relevant indicators, such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), thiobarbituric acid reactive substances (TBARS) and matrix metalloproteinases (MMPs), were then used to evaluate the ability of DOPs to repair photodamage. The results indicated that DOPs significantly reduced erythema and protected the skin from dryness and therefore exhibits a significant anti-photoaging effect. In addition, the expression of CAT, SOD, and GSH-Px increased while TBARS and MMPs levels decreased in DOPs-treated mice. This demonstrated that DOPs can inhibit photodamage in the skin of hairless mice. DOPs could be used as a potential therapeutic agent to protect the skin against UV-induced photoaging.