Background: Age-related macular degeneration (AMD), a major eye degenerative disease, ultimately causes irreversible vision loss. Baicalin was identified to attenuate laser-induced chorodial neovascularization, indicating a therapeutic role in AMD. However, the exact mechanisms for baicalin in AMD remain unknown. Methods: MTT assay was performed to access the suitable concentration of baicalin or Aβ for treating ARPE-19 cells. CCK-8, morphology, and flow cytometry analysis were performed to evaluate cell viability and pyroptosis of baicalin in Aβ-envoked ARPE-19 cells. Quantitative real-time polymerase chain reaction and western blot analysis were subjected to measure the correlation between miR-223 and NLRP3. Luciferase reporter assay was performed to determine their direct relationship. Western blot analysis was subjected to determine pyroptosis-related proteins. Results: Baicalin inhibited Aβ-envoked pyroptosis in ARPE-19 cells. Mechanistically, baicalin significantly induced upregulation of miR-223 and downregulation of NLRP3, thus suppressing pyroptosis triggered by NLRP3 inflammasome signaling, yet such beneficial effects were reversed by miR-223 knockdown. Additionally, MCC950, a NLRP3 inhibitor, restored anti-pyroptosis activity of baicalin under miR-223 silencing. Conclusion: Baicalin alleviates intracellular pyroptosis and viability damage resulted from Aβ inducement in human retinal pigment epithelium cells via negative crosstalk of miR-223/NLRP3 inflammasome signaling, indicating that baicalin may be considered as a potential candidate for AMD therapy.