The failure of the separator membrane by rupture or thermal runaway is the prime cause of concern for the lithium battery system. In this work, we model the mechanical behavior and ionic conductance of the separator membrane under compression and its influence on the lithium cell thermal performance. The separator membrane is modeled as an open-cell foam to correlate the mechanical deformation under compressive loads and ionic conductivity. Predicted correlation between mechanical deformation and ionic conductivity is compared with experimental reports of membrane performance. Next, the validated model is used to simulate the thermal performance of lithium-ion pouch cells. Thermal response is predicted for a number of different pouch cell configurations with graphite (C) as anode; cathode chosen from lithium manganese oxide (LMO), lithium cobalt oxide (LCO) or lithium ferrous phosphate (LFP); and separator membrane chosen from monolayer polypropylene (PP), monolayer polyethylene (PE), trilayer, non-woven or ceramic-coated. The thermal response is used to predict the average cell temperature under an applied compressive load. Design maps that plot the maximum cell temperature over a range of applied load for different rates of charging and cooling conditions are prepared and used to identify the design conditions leading to separator meltdown and thermal runaway.