Platinum-based chemotherapeutics remain the backbone breast cancer treatment. Nevertheless, their clinical efficacy is frequently limited by systemic toxicity, drug resistance, and poor selectivity. We synthesized Asplatin, a platinum(IV) prodrug, by conjugating cisplatin with acetylsalicylic acid (aspirin), to combine the DNA-damaging activity of platinum with the anti-inflammatory and chemosensitizing properties of aspirin. This offers synergistic anticancer potential. Nevertheless, the systemic premature reduction of asplatin and its limited tumor-specific activation hinder its therapeutic translation. In this work, we engineered thermo-responsive nanoliposomes encapsulating asplatin to enable hyperthermia-triggered drug release and enhanced anticancer efficacy against triple-negative breast cancer (TNBC). Nanoliposomes, composed of DPPC, DSPE-PEG2000, and cholesterol were statistically optimized using a Box–Behnken design. The produced nanoscale vesicles have an average size of 114.1 ± 1.6 nm, low dispersity (PDI = 0.15 ± 0.02), and high drug entrapment efficiency (84.1 ± 2.8%). The optimized formulation exhibited excellent stability at physiological temperature and a pronounced heat-triggered release profile, with minimal drug leakage at 37 °C and rapid release reaching approximately 90% at 40 °C. In vitro evaluation in MDA-MB-231 triple-negative breast cancer cells revealed that hyperthermia-activated asplatin-loaded liposomes significantly improved cytotoxicity, achieving an IC₅₀ of 0.9 mg mL⁻¹, in contrast to 3.83 mg mL⁻¹ for free asplatin under identical thermal conditions. This corresponds to a four-fold increase in anticancer potency. Mechanistically, the hybrid cisplatin–aspirin prodrug delivered via thermo-responsive liposomes strongly activated the intrinsic apoptotic pathway, as evidenced by significant upregulation of Bak (5.6-fold), Bax (7.2-fold), and P53 (1.3-fold), coupled with significant reduction of BCL-2 and BCL-xL (up to 85%). Overall, this study highlights the therapeutic potential of combining cisplatin–aspirin synergy with heat-triggered nanodelivery, offering a promising approach to boost platinum-based chemotherapy while minimizing off-target toxicity in aggressive breast cancers.