Background: Keloid is a fibrotic disease characterized by hyperproliferative fibroblasts. Notoginsenoside R1 (NGR1) possesses inhibitory roles on cell proliferation. Thus, the research sought to assess the mechanism of action of NGR1 against keloid. Materials and Methods: Cell viability of normal and keloid fibroblasts pretreated with different NGR1 concentrations was determined by Cell Counting Kit-8 assay. Cell cycle, apoptosis rate, and tube length were detected using flow cytometry and tube formation assay. Vascular endothelial growth factor (VEGF) expression was measured by quantitative real-time polymerase chain reaction and western blot. To verify the reversal effect of VEGF on NGR1, KEL FIB cells were transfected with pcDNA3-VEGF plasmids following treatment with 40 μM NGR1; subsequently, the above indicators were determined again. Results: NGR1 decreased cell viability, and 20, 30, and 40 μM NGR1 concentrations were selected for the next investigation. After KEL FIB was treated with NGR1, the apoptosis rate was increased, cell cycle was arrested, and tube formation was suppressed in a dose-dependent manner. The expression of VEGF was also suppressed. In further experiments, cell cycle and tube formation were promoted and apoptosis rate was decreased in NGR1-treated cells when VEGF was overexpressed. Conclusion: NGR1 may play as an inhibitor of endogenous VEGF, and NGR1 exerts its inhibitory effects on keloid fibroblasts by downregulating VEGF.