Chronic and complex disease states requiring prolonged pharmacotherapy present significant challenges to patient adherence and therapeutic outcomes when managed with conventional daily or multiple-daily dosing regimens. Long-acting injectable formulations utilizing biodegradable polymers address these limitations by providing sustained drug release over weeks to months following a single administration. This review examines the scientific principles, formulation strategies, and therapeutic applications of biodegradable polymer-based sustained-release injectable systems. Synthetic polymers including poly (lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly(caprolactone) (PCL), and polyethylene glycol derivatives are analyzed alongside natural polymers such as chitosan, gelatin, and alginate, with emphasis on degradation kinetics, biocompatibility, and material properties governing release behavior. Formulation approaches encompass preformed microparticles prepared by emulsion-solvent evaporation and spray drying, in situ forming depots utilizing phase inversion or thermosensitive gelation, and implantable solid matrices including biodegradable rods and drug–polymer composites. Release mechanisms integrate diffusion-controlled processes governed by Fickian principles, degradation-controlled release through hydrolytic chain scission exhibiting bulk or surface erosion characteristics, and swelling-mediated transport in hydrogel systems. Therapeutic applications span oncology with leuprolide acetate depots for prostate cancer, infectious diseases including long-acting antiretroviral formulations for HIV prophylaxis and treatment, and chronic disease management exemplified by sustained-release antipsychotics for schizophrenia and diabetes therapies. Comparative evaluation of microspheres, in situ depots, hydrogels, and implants reveals distinct profiles in drug loading capacity, release duration, and clinical translation potential. Challenges including burst release mitigation, manufacturing scale-up, and regulatory pathways are addressed alongside emerging smart biodegradable systems incorporating stimuli-responsive elements for precision-controlled long-acting therapeutics.