Non-steroidal anti-inflammatory drugs (NSAIDs), such as piroxicam (PX), are widely used but are limited by gastrointestinal and hepatic toxicity. Electron beam (e-beam) irradiation can induce structural diversification of small molecules, potentially generating derivatives with altered pharmacological profiles. We investigated the biological activities of e-beam-irradiated piroxicam (PX-EB) and two purified derivatives—Radioxicam-1 (Rdx-1) and Radioxicam-2 (Rdx-2). High-performance liquid chromatography, nuclear magnetic resonance, and high-resolution electrospray ionization mass spectrometry analyses supported the formation and structural assignment of Rdx-1 and Rdx-2 as PX-derived radiolytic products. In bone marrow-derived dendritic cells, PX, PX-EB, Rdx-1, and Rdx-2 exhibited no significant cytotoxicity at concentrations up to 25 μM. Rdx-1 and Rdx-2 significantly suppressed pro-inflammatory cytokine (tumor necrosis factor α, interleukin (IL)-6, and IL-12) production more strongly than intact PX. Rdx-1 and Rdx-2 also reduced nitric oxide production. Mechanistically, they preferentially modulated COX-2 and decreased prostaglandin E2 secretion, while showing limited effects on constitutive COX-1; they also influenced selected inflammatory signaling pathways including p38 mitogen-activated protein kinases phosphorylation and nuclear factor-κB accumulation. In a lipopolysaccharide-induced sepsis model, PX-EB showed mediator-specific systemic anti-inflammatory activity and a relatively favorable hepatic biochemical profile, compared with PX. Collectively, these findings suggest that e-beam irradiation generates structurally distinct PX-derived radiolytic products with selective immunomodulatory activities, supporting further investigation of irradiation-based structural modification as a strategy to expand the pharmacological utility of existing NSAID.