The eggshell membrane (ESM) is a natural bioactive material, which is increasingly utilized for various biomedical applications. However, the poor solubility of ESM limits the bioavailability of its constituents and reduces the expression of their potential bioactivity. In this study, we utilized an innovative green strategy to separate ESM from shell, and processed ESM for size reduction by cryo-grinding and homogenization to produce particalized eggshell membrane (PEM) approaching submicron dimensions, with enhanced anti-inflammatory activity and increased antimicrobial activity against skin associated pathogens. Gram-positive Staphylococcus aureus (log10 reduction = 4.5 ± 0.3) was more sensitive to PEM as compared to Gram-negative Pseudomonas aeruginosa (log10 reduction = 2.1 ± 0.3). PEM elicited a dose-dependent reduction in NO accumulation in LPS-induced RAW 264.7 macrophages, suggesting an anti-inflammatory response to ESM particles. These findings suggest that processed PEM possesses great potential as a topical ingredient in skincare applications to maintain skin health by reducing bacterial infections and inflammation.