Purpose <p>Breast cancer remains a leading cause of cancer-related death in women, with conventional chemotherapy facing challenges like limited efficacy and high toxicity. Drug delivery systems (DDS) offer promising alternatives by enhancing drug targeting, increasing bioavailability, and minimizing adverse effects. This systematic review and meta-analysis evaluates the effectiveness of DDS in inhibiting tumor growth in preclinical breast cancer models, comparing targeted and non-targeted approaches, as well as the most common DDS platforms.</p> Method <p>A comprehensive literature search identified 62 preclinical studies on the efficacy of drug delivery systems (DDS) in breast cancer treatment. Key variables such as DDS type, chemotherapeutic agents, targeting strategies, and administration routes were analyzed, with subgroup analyses based on targeting approaches and administration methods. A risk of bias assessment was also performed to evaluate study quality.</p> Results <p>Drug delivery systems (DDS) significantly enhanced tumor growth inhibition compared to free drugs, with targeted DDS showing superior efficacy. Liposomes and epirubicin-loaded DDS exhibited the greatest tumor suppression, and aptamers were the most effective targeting ligands. Intraperitoneal administration showed a slight advantage over intravenous delivery. Methodological flaws, such as inadequate randomization and blinding, were noted in several studies.</p> Conclusions <p>DDS, particularly with targeted delivery strategies, significantly improve chemotherapeutic efficacy in preclinical breast cancer models. Liposomes, epirubicin-loaded DDS, and aptamers are promising, but variability in study designs necessitates more rigorous and standardized methodologies for better translational relevance.</p>