In this work, three-dimensional thermal simulations of single 18650 lithium-ion battery cell and 75 V lithium-ion battery pack composed of 21 18650 battery cells are performed based on a multi-scale multi-domain (MSMD) battery modeling approach. Different cooling approaches’ effects on 18650 lithium-ion battery and battery pack thermal management under fast discharging and external shorting conditions are investigated and compared. It is found that for the natural convection, forced air cooling, and/or mini-channel liquid cooling approaches, the temperature of battery cell easily exceeds 40 °C under 3C rate discharging condition. While under external shorting condition, the temperature of cell rises sharply and reaches the 80 °C in a short period of time, which can trigger thermal runaway and may even lead to catastrophic battery fire. On the other hand, when the cooling method is single-phase direct cooling with FC-72 as coolant or two-phase immersed cooling by HFE-7000, the cell temperature is effectively limited to a tolerable level under both high C rate discharging and external shorting conditions. In addition, two-phase immersed cooling scheme is found to lead to better temperature uniformity according to the 75 V battery pack simulations.