Thermal runaway propagation mitigation is a prerequisite in battery development for electric vehicles to meet legal requirements and ensure vehicle occupants’ safety. Thermal runaway propagation depends on many factors, e.g., cell spacing, intermediate materials, and the entire cell stack setup. Furthermore, the choice of cell chemistry plays a decisive role in the safety design of a battery system. However, many studies considering cell chemistry only focus on the cell level or neglect the energetic impacts of safety measures on system integration. This leads to a neglect of the conflict of objectives between battery safety and energy density. In this article, a comprehensive analysis of the thermal runaway propagation in lithium-ion batteries with NMC-811 and LFP cathodes from a Mini Cooper SE and Tesla Model 3 SR+ is presented. The focus is set on the identification of differences in battery safety, the derivation of safety requirements, and the evaluation of their impact on system integration. A comparative analysis identified significantly higher safety requirements for Graphite NMC-811 than for Graphite LFP cell chemistries. Regarding cell energy, thermal runaway reaction speed is nine times faster in NMC-811 cells and five times faster considering the whole propagation interval than LFP cells. However, since LFP cell chemistries have significantly lower energy densities than ternary cell chemistries, it must be verified whether the disadvantages in energy density can be compensated by advanced system integration. An analysis of cell-to-pack ratios for both cell chemistries has revealed that, based on average values, the gravimetric disadvantages are reduced to 16%, and the volumetric disadvantages can be completely compensated for at the pack level. However, future research should further focus on this issue as an accurate safety-related design depending on cell chemistry could enable a cost–benefit evaluation under the constraints of safety standards in the development of batteries for electric vehicles.