Inflammation underlies the progression of both acute and chronic diseases, yet conventional therapies remain limited by systemic side effects, poor compliance, and insufficient responsiveness to dynamic pathological cues. Nitric oxide (NO), a gaseous mediator with high diffusivity and membrane permeability, is aberrantly overproduced in diverse inflammatory conditions and thus represents a promising trigger for responsive drug delivery. Here, we present a NO-responsive microneedle (NOR-MN) platform that exploits pathological NO for controlled transdermal therapy. The system integrates a NO-cleavable crosslinker that degrades selectively in NO-rich environments, enabling NO-dependent release of encapsulated drugs while simultaneously scavenging excess NO to mitigate inflammation. This dual-functional design combines disease-responsive delivery with intrinsic anti-inflammatory activity, offering a minimally invasive and therapeutically adaptable platform. The therapeutic potential of NOR-MNs was validated in both acute and chronic inflammatory models. In lipopolysaccharide-induced peritonitis, dexamethasone-loaded NOR-MNs achieved NO-triggered release, suppressed cytokine production, alleviated hepatic toxicity, and improved tissue pathology. In diabetes mellitus, insulin-loaded NOR-MNs responded to elevated NO levels to restore glucose homeostasis and enhanced insulin responsiveness in vitro. Collectively, these findings establish NO-responsive microneedles as an innovative stimuli-responsive strategy with broad applicability for the treatment of inflammation-driven diseases.