In recent years, research on lithium–ion (Li-ion) battery safety and fault detection has become an important topic, providing a broad range of methods for evaluating the cell state based on voltage and temperature measurements. However, other measurement quantities and close-to-application test setups have only been sparsely considered, and there has been no comparison in between methods. In this work, the feasibility of a multi-sensor setup for the detection of Thermal Runaway failure of automotive-size Li-ion battery modules have been investigated in comparison to a model-based approach. For experimental validation, Thermal Runaway tests were conducted in a close-to-application configuration of module and battery case—triggered by external heating with two different heating rates. By two repetitions of each experiment, a high accordance of characteristics and results has been achieved and the signal feasibility for fault detection has been discussed. The model-based method, that had previously been published, recognised the thermal fault in the fastest way—significantly prior to the required 5 min pre-warning time. This requirement was also achieved with smoke and gas sensors in most test runs. Additional criteria for evaluating detection approaches besides detection time have been discussed to provide a good starting point for choosing a suitable approach that is dependent on application defined requirements, e.g., acceptable complexity.