Nanotechnology has emerged as an innovative tool capable of overcoming the limitations of traditional drug delivery systems by enabling the manipulation of materials at the nanometric scale, giving them unique properties such as enhanced solubility, increased stability, and drug targeting to the therapeutic site of action. Among the most significant advantages that nanosystems have, is the fact that they allow the co-encapsulation of multiple drugs within a single nanosystem, harnessing their synergistic effects, contributing significantly to the reduction of potential side effects associated with conventional multiple therapy and with a potential impact on patient compliance. This literature review explores studies analyzing the potential of simultaneous delivery of three drugs within different types of nanosystems, for the treatment of chronic and infectious diseases, namely rheumatoid arthritis, psoriasis, human immunodeficiency virus infection, Helicobacter pylori infection, and anti-inflammatory therapies, as well as conditions such as secondary degeneration following neurotrauma, being the first of its kind, and filling an existing gap in the scientific literature. Parameters such as particle size, polydispersity index, zeta potential, encapsulation efficiency, and in vitro and in vivo efficacy and safety assays consistently demonstrated efficient co-encapsulation of multiple drugs with potential pharmacological synergy, controlled and prolonged drug release, and the capacity for therapeutic site-specific targeting, thereby increasing bioavailability and enabling the reduction of systemic adverse effects. While transition into clinical practice still faces regulatory hurdles, and in-depth long-term safety assessments are needed, overall nanosystems could play a leading role in the future of nanomedicine towards more effective and personalized therapies.