This study developed and optimized an innovative oral pH-dependent drug delivery system utilizing rosuvastatin-loaded chitosan nanoparticles (RSV-CSNPs) coated with sodium alginate (ALG). The goal was to protect RSV-CSNPs from degradation in the acidic gastric environment and facilitate targeted sustained release in the colon to address inflammatory bowel disease. Nanoparticles were initially prepared by ionic gelation. A subsequent ALG coating process was optimized using a 2 factorial design. The optimal ALG-coated formulation demonstrated minimal drug loss (0.88% ± 0.09%), desirable particle size (407.2 ± 1.95 nm), and suitable zeta potential (-27.13 ± 1.36 mV). release tests highlighted the superiority of ALG-coated RSV-CSNPs, with significantly reduced RSV release in simulated gastric fluid (6.8% ± 1.06% after 2 h) compared to uncoated nanoparticles (38.45% ± 1.79%), affirming the protective effectiveness of the ALG coating. Extended-release studies at colonic pH (6.8) demonstrated sustained RSV release suitable for colon-specific targeting. assessments in a dextran sodium sulfate (DSS)-induced rat model of colitis revealed that ALG-RSV-CSNPs significantly outperformed both plain RSV and RSV-CSNPs. Treatment notably decreased colonic inflammation, disease severity scores, macroscopic damage, and oxidative stress indicators. Additionally, histopathological analyses showed remarkable restoration of colon tissue integrity, crypt preservation, and mucosal protection in animals treated with ALG-RSV-CSNPs. Mechanistically, ALG-RSV-CSNPs effectively attenuated colitis by significantly inhibiting the HMGB1-triggered RAGE/TLR4-NFκB inflammatory signaling pathway. Treatment resulted in substantial reductions in key inflammatory markers, including HMGB1, RAGE, TLR4 expression, NFκB activity, pro-inflammatory cytokines (TNF-α and IL-6), and apoptosis marker caspase-3. The anti-inflammatory actions were further supported by reduced neutrophil infiltration, lipid peroxidation, and enhanced antioxidant enzyme activities (SOD and GSH levels). The study identified HMGB1, RAGE, TLR4, and NFκB as critical biomarkers predicting disease activity. Correlation analysis highlighted strong positive associations among these markers, underscoring their collective involvement in colitis pathogenesis and emphasizing the multitarget therapeutic efficacy of ALG-RSV-CSNPs. Overall, this study demonstrates that the optimized pH-responsive ALG-coated RSV-CSNPs significantly enhance the therapeutic outcomes of RSV in colonic inflammation through targeted delivery and sustained release. These nanoparticles represent a promising strategy for effectively managing ulcerative colitis and related inflammatory bowel diseases. Future clinical studies are warranted to validate these findings and facilitate translation into human therapeutic applications.