The protective effects of Neorhodomela aculeata methanolic extract (N. aculeata) on IL-1β and IFN-γ induced β-cell cytotoxicity were examined in a rat insulinoma (RIN) cell line and islets. In the cytokine-treated RIN cells, nitric oxide (NO) production was reduced about 94% at 50 μg/ml of N. aculeata and its suppressive effect was ten times greater as compared to other effective oriental herbs, such as C. cinnamoni and A. capillaries. The inhibitory effects of NO production occurred through the suppression of iNOS (inducible nitric oxide synthase) gene expression which has been confirmed with the changes of iNOS mRNA and protein levels. N. aculeata attenuated the cytokine-induced increase in nuclear factor-kappa B (NF-κB) binding activity, p50 and p65 subunit levels in their nuclei, and at inhibitory kappa B alpha degradation in the cytosol. N. aculeata also attenuated the levels of phosphorylated signal transducer and activator of transcription (STAT)-1 and -3 in whole RIN cells as well as the nuclear translocation of the STAT proteins. Therefore, the cytoprotective effects of N. aculeata were possibly mediated through the suppression of NF-κB and STAT pathways. These findings suggest the beneficial effects of N. aculeata when used for the prevention or attenuation of inflammatory and Type 1 diabetogenic processes.