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Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by epithelial damage, excessive cytokine release, and dysregulated inflammasome activation. Herein, we report the design, synthesis, and multi-targeted biological evaluation of three novel mesalamine–NSAID hybrid derivatives (D1, D3, and D4) as potential therapeutic agents for UC. Structural hybridization was employed to enhance colonic targeting, suppress NLRP3 inflammasome signaling, and reduce systemic toxicity. All compounds were characterized and screened for anti-inflammatory efficacy via qRT-PCR analysis of key inflammasome-related genes (NLRP3, IL1B, IL-18, Caspase-1) in LPS-activated macrophages. Compound D3 exhibited the most potent downregulation profile, supported by molecular docking studies showing favorable interactions with NLRP3 and caspase-1. Antioxidant activity was evaluated using the DPPH assay, with D3 demonstrating the lowest IC 50 (19.20 µg/mL). Antimicrobial and brine shrimp lethality assays confirmed the moderate cytotoxicity profiles and pathogen-inhibitory potential of all compounds. Collectively, these results highlight D3 as a dual-action anti-inflammatory and antioxidant agent capable of modulating key immune and redox pathways implicated in UC pathogenesis. The study supports mesalamine–NSAID hybridization as a promising strategy for developing next-generation UC therapeutics with improved efficacy and safety profiles.