Chronic inflammation contributes to the pathogenesis of many diseases, including apparently unrelated conditions such as metabolic disorders, cardiovascular diseases, neurodegenerative diseases, osteoporosis, and tumors, but the use of conventional anti-inflammatory drugs to treat these diseases is generally not very effective given their adverse effects. In addition, some alternative anti-inflammatory medications, such as many natural compounds, have scarce solubility and stability, which are associated with low bioavailability. Therefore, encapsulation within nanoparticles (NPs) may represent an effective strategy to enhance the pharmacological properties of these bioactive molecules, and poly lactic-co-glycolic acid (PLGA) NPs have been widely used because of their high biocompatibility and biodegradability and possibility to finely tune erosion time, hydrophilic/hydrophobic nature, and mechanical properties by acting on the polymer’s composition and preparation technique. Many studies have been focused on the use of PLGA-NPs to deliver immunosuppressive treatments for autoimmune and allergic diseases or to elicit protective immune responses, such as in vaccination and cancer immunotherapy. By contrast, this review is focused on the use of PLGA NPs in preclinical in vivo models of other diseases in which a key role is played by chronic inflammation or unbalance between the protective and reparative phases of inflammation, with a particular focus on intestinal bowel disease; cardiovascular, neurodegenerative, osteoarticular, and ocular diseases; and wound healing.