Inflammation is a hallmark of various pathological conditions, including cancer, cardiovascular diseases, neurodegenerative disorders, and autoimmune diseases. Reactive oxygen species (ROS) are crucial mediators in the inflammatory microenvironment, playing a pivotal role in both normal cellular processes and disease progression. Targeting ROS overproduction in inflamed tissues has emerged as a promising therapeutic strategy. Polymeric nanoparticles (NPs) responsive to ROS levels in pathological tissues have gained substantial attention as precision drug delivery systems, capable of ensuring controlled, site-specific drug release. This review provides a comprehensive mechanistic insight into ROS-responsive polymeric nanoparticles, examining their structural design, functionalization strategies, drug release mechanisms, and potential for targeted therapies in inflammatory conditions. Furthermore, we discuss recent advancements, challenges, and future directions in utilizing ROS-responsive polymeric nanoparticles for precision therapeutics, highlighting their transformative potential in clinical applications.