<p>Zinc oxide nanoparticles (ZnONPs) are widely used in sunscreens and cosmetics; however, increasing evidence suggests their potential to induce skin toxicity, particularly under conditions of skin function disruption. Here, we investigated the mechanisms underlying allergic skin inflammation triggered by repeated ZnONPs exposure following UVR damage using an in vivo hairless mouse model and in vitro Adverse Outcome Pathway (AOP)-based new approach methodologies (NAMs). Co-exposure to ZnONPs and UVR caused persistent barrier dysfunction, epidermal hyperplasia, mast cell degranulation, elevated serum IgE levels, and increased expression of Th2-associated cytokines (IL-4, IL-13, and IL-17A), indicating enhanced allergic skin inflammation. KeratinoSens and h-CLAT assays demonstrated that UVR augmented ZnONPs-induced keratinocyte activation (key event 2) and dendritic cell activation (key event 3). Mechanistically, ZnONPs combined with UVR induced mitochondrial dysfunction, oxidative stress, and canonical NLRP3 inflammasome activation in keratinocytes, leading to pyroptotic cell death. Instead, dendritic cells activated an alternative TLR4–RIPK1–FADD–caspase-8 inflammasome pathway independent of pyroptosis. Collectively, these findings demonstrate that ZnONPs can function as sensitizers under barrier-compromised conditions through different inflammasome pathways, highlighting the need to adapt current skin sensitization testing strategies for nanomaterials and to incorporate mechanistic endpoints into future risk assessment frameworks.</p>