Although the 46800-type Li-ion batteries have superior attributes, including high driving range, energy density, and fast charging capability, it is plagued by higher heat generation during discharge impacting performance, efficiency, and lifespan. To address this problem, a novel thermal management system is proposed utilizing direct/indirect liquid cooling with water, CuO nanofluid, and HFE-7100. Meshed separator plates are developed in the direct cooling channel to improve thermal uniformity and mitigate hot spots on LIBs. The numerical evaluation considers effects such as C-rate, coolant, separator wall, flow rates, flow direction, and ambient temperature on the thermal performance of the LIB pack. During a 3C discharge operation, compared to 1C, the LIB pack experiences a 7 °C increase in maximum temperature and a 4.1 °C temperature difference. However, with a 4% CuO nanofluid, these values decrease by 4.9 °C and 3 °C respectively, compared to water. A circular meshed separator wall improved the thermal performance of the battery pack by 22.7% compared to the non-wall condition. The inflow velocities of the direct and indirect cooling channels are increased from 0.2 to 0.3 m/s and from 0.1 to 0.2 m/s, respectively, which led to the 11.5% enhancement of the LIB pack’s thermal efficiency. Finally, the thermal performance of the proposed cooling system is assessed by considering various ambient temperatures ranging from 25 °C to 40 °C for the LIB pack. The results indicated that the optimized cooling system can maintain the maximum temperature of the LIB pack below 40 °C, even at an ambient temperature of 35 °C.