Despite the variant incidence of CRC, among different countries it remains the third most common type of cancer and leading cause of cancer deaths worldwide. Cisplatin, the most common chemotherapy drug used in solid tumor treatment, is used in combination with other drugs to produce synergistic effects in eradicating cancer cells, while keeping its side effects to a minimal. Nano-cubosomes, thanks to the advantages of their liquid crystalline porous nano-architecture and capability for multi-drug encapsulation, appear to be of interest as nanocarriers for anticancer therapies. Hence, delivering cisplatin, as nano-cubosomes, concomitantly with other chemo-dugs can lead to a rationally designed therapy for chemo-resistant cancers and might overcome problems associated with conventional cisplatin treatment. The aim of the present study was to construct nano-cubosomes bearing cisplatin, metformin and cisplatin-metformin combination and investigate their effect on proliferation in Caco-2 and HCT-116 cell lines, as well as, tumorigenesis-associated metabolic markers in HCT-116 CRC cell lines. Results from this study revealed that nanocubosomal formulations exhibited superior cytotoxic effect compared to unformulated cisplatin. This cytotoxic effect was profound upon incorporation of metformin, an mTOR inhibitor, in cisplatin nano-cubosomes. The induced CRC cell apoptosis was through inhibition of several metabolic pathways, namely, AMPK/mTOR and Akt/mTOR. Drugloaded nano-cubosomes ensued depletion in glucose and energy levels that led to AMPK activation and thus mTOR inhibition. mTOR was additionally inhibited via suppression of p-Akt levels after nano-cubosomal treatment. Moreover, drug-loaded nano-cubosomes produced a notable escalation in ROS levels, evident as an increase in NADPH oxidase, inhibition of LDH and a consequential upsurge in caspase-3. These results demonstrated the influence exerted by low concentrations of cisplatin-loaded nano-cubosomes on CRC cell survival and enhancement of their cytotoxicity upon metformin addition.