<p>Renal ischemia–reperfusion injury (RIRI) is a prevalent and damaging pathological process in clinical practice, significantly impairing renal recovery and long-term prognosis. The pathogenesis of IRI involves multiple factors, including oxidative stress, inflammatory activation, cell death pathways, and microcirculatory disturbances. Conventional therapies have limited efficacy targeting individual factors and fail to provide comprehensive intervention within the complex RIRI pathological network. Recently, nanoparticles—due to their excellent biocompatibility, targeting ability, and environment-responsive characteristics—have become promising tools for precise diagnosis and multimodal therapy in RIRI. This review systematically summarizes recent advances in nanoparticle-based strategies for RIRI, emphasizing their mechanistic roles in modulating key pathological processes. These mechanisms involve ROS scavenging to reduce oxidative stress, inhibition of NF-κB to suppress inflammation, stabilization of mitochondria to prevent apoptosis, regulation of ferroptosis, and restoration of microcirculatory function. Furthermore, we highlight the potential of nanoparticles in diagnostic applications, such as enhancing lesion-specific localization and molecular imaging accuracy through intelligent stimulus-responsive systems. The article also discusses major challenges in translating nanotechnology clinically, including in vivo stability, biosafety, and large-scale production. Finally, we outline future research directions, such as the development of smart responsive platforms, multi-target synergistic therapeutic systems, and strategies for remodeling the renal immune microenvironment. Overall, this work aims to establish a theoretical foundation to advance nanotechnology’s clinical application and mechanistic understanding in RIRI management.</p>