Poly(lactic-co-glycolic acid) (PLGA) is a widely used biodegradable and biocompatible copolymer in drug delivery systems (DDSs). This review highlights the critical physicochemical properties of PLGA, including molecular weight, intrinsic viscosity, monomer ratio, blockiness, and end caps, which significantly influence drug release profiles and degradation times. The article covers the extensive literature on the application of PLGA in delivering small-molecule drugs, proteins, peptides, antibiotics, and antiviral drugs. It also discusses the role of PLGA-based DDSs in treating various diseases, including cancer, neurological disorders, pain, and inflammation. Incorporating drugs into PLGA nanoparticles and microspheres enhances therapeutic efficacy, reduces toxicity, and improves patient compliance. PLGA-based DDSs show great promise for the treatment and management of multiple chronic conditions. PLGA is synthesized through ring-opening polymerization of lactide and glycolide or direct polycondensation of lactic acid and glycolic acid. Its degradation occurs through hydrolysis of ester linkages, leading to the release of lactic acid and glycolic acid, which are metabolized through the Krebs cycle. PLGA-based DDSs can be tailored to release drugs at controlled rates, protect them from degradation, and enhance stability. Various modifications, such as surface modification, coating, blending, functionalization, and cross-linking, have been explored to enhance the properties of PLGA-based DDSs. PLGA-based DDSs have been successfully used to deliver small-molecule drugs, vaccines, proteins, and peptides. Examples include Risperdal Consta (risperidone) and the peptide-containing microspheres of Lupron Depot (leuprolide). Clinical trials have shown promising results in exploring new indications for existing products or investigating potential new therapeutics. PLGA-based DDSs have also been used to deliver paclitaxel and curcumin, improving their solubility and bioavailability. For proteins and peptides, PLGA-based DDSs have been used to deliver leuprolide acetate and other therapeutic agents, providing sustained release profiles. PLGA-based DDSs have been applied in the treatment of pain, cancer, neurological disorders, and inflammation. For example, sustained-release ropivacaine (SRR) has been used to treat neuropathic pain, while PLGA-based nanofibers have been used to deliver dexamethasone and ropivacaine for prolonged analgesic effects. In cancer treatment, PLGA-based DDSs have been used to deliver photothermal agents and anticancer drugs, improving therapeutic outcomes. For neurological disorders, PLGA-based DDSs have been used to deliver drugs across the blood-brain barrier, improving brain delivery and bioavailability. In inflammation, PLGA-based DDSs have been used to deliver anti-inflammatory agents, such as tetramethylpyrazine, for prolonged therapeutic effectsPoly(lactic-co-glycolic acid) (PLGA) is a widely used biodegradable and biocompatible copolymer in drug delivery systems (DDSs). This review highlights the critical physicochemical properties of PLGA, including molecular weight, intrinsic viscosity, monomer ratio, blockiness, and end caps, which significantly influence drug release profiles and degradation times. The article covers the extensive literature on the application of PLGA in delivering small-molecule drugs, proteins, peptides, antibiotics, and antiviral drugs. It also discusses the role of PLGA-based DDSs in treating various diseases, including cancer, neurological disorders, pain, and inflammation. Incorporating drugs into PLGA nanoparticles and microspheres enhances therapeutic efficacy, reduces toxicity, and improves patient compliance. PLGA-based DDSs show great promise for the treatment and management of multiple chronic conditions. PLGA is synthesized through ring-opening polymerization of lactide and glycolide or direct polycondensation of lactic acid and glycolic acid. Its degradation occurs through hydrolysis of ester linkages, leading to the release of lactic acid and glycolic acid, which are metabolized through the Krebs cycle. PLGA-based DDSs can be tailored to release drugs at controlled rates, protect them from degradation, and enhance stability. Various modifications, such as surface modification, coating, blending, functionalization, and cross-linking, have been explored to enhance the properties of PLGA-based DDSs. PLGA-based DDSs have been successfully used to deliver small-molecule drugs, vaccines, proteins, and peptides. Examples include Risperdal Consta (risperidone) and the peptide-containing microspheres of Lupron Depot (leuprolide). Clinical trials have shown promising results in exploring new indications for existing products or investigating potential new therapeutics. PLGA-based DDSs have also been used to deliver paclitaxel and curcumin, improving their solubility and bioavailability. For proteins and peptides, PLGA-based DDSs have been used to deliver leuprolide acetate and other therapeutic agents, providing sustained release profiles. PLGA-based DDSs have been applied in the treatment of pain, cancer, neurological disorders, and inflammation. For example, sustained-release ropivacaine (SRR) has been used to treat neuropathic pain, while PLGA-based nanofibers have been used to deliver dexamethasone and ropivacaine for prolonged analgesic effects. In cancer treatment, PLGA-based DDSs have been used to deliver photothermal agents and anticancer drugs, improving therapeutic outcomes. For neurological disorders, PLGA-based DDSs have been used to deliver drugs across the blood-brain barrier, improving brain delivery and bioavailability. In inflammation, PLGA-based DDSs have been used to deliver anti-inflammatory agents, such as tetramethylpyrazine, for prolonged therapeutic effects