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The fruit of Lycium barbarum L. (goji berry) is a traditional Chinese medicine and is often used to improve vision. While various goji cultivars may differentially treat retinal degeneration, however their comparative effectiveness remains unclear. To evaluate the protective effects of four goji cultivars on NaIO 3 -induced retinal degeneration mouse model and identify the most therapeutically potent cultivar. The principal compounds in the extracts of four goji cultivars were characterized by UPLC-Q-TOF/MS. A retinal degeneration mouse model was established via NaIO 3 injection. Dark-light transition and TUNEL assays were used to assess visual function and retinal apoptosis. The levels of antioxidative, inflammatory, and angiogenic markers in serums and eyeballs were measured. Hierarchical cluster analysis, principal component analysis and partial least squares-discriminant analysis were used to objectively compare the treatment responses. Sixteen compounds were identified in goji berry extracts. All goji berry extracts could reverse NaIO 3 -induced visual impairment, retinal damage and apoptosis. The samples from the cultivar of Ningqi No.1 significantly modulated oxidative stress, inflammation, and vascular endothelial growth factor levels, which are more effectively than the other cultivars based on integrated multivariate profiling. Ningqi No.1 demonstrated a stronger protective effect on mouse retina than other goji cultivars, and is a potential variety for further research on the treatment of retinal degeneration. [Display omitted] • Therapeutic effects of 4 cultivars of Goji were compared on retinal degeneration mice. • Retinal morphometry assessed via optical coherence tomography in retinal degeneration mice. • Multivariate analysis objectively profiled protection of Goji cultivars. • Goji berry from Ningqi No.1 was better in treating retinal degeneration than the other 3 cultivars. [ABSTRACT FROM AUTHOR]