Thermal interface materials (TIMs) comprise an important role in the thermal management of a myriad of electronic devices, and their ability to ensure both enhanced thermal conductance and reliable adhesion at thermal interfaces is paramount to the reliability of electronics packaging. Like most aspects of a typical electronics package, on/off cycles undergone during a device’s operation induce thermo-mechanical stresses that can negatively affect the integrity of the package. Due to the inherently low adhesive strength and structural integrity of polymer TIMs, they present a likely point of failure when succumbed to these interfacial stresses. Methods for quantifying TIM degradation during mechanical cycling have been quite infrequent in literature; an accelerated and repeatable method for measuring the thermal reliability of TIMs would prove to be beneficial. Herein, we present a methodology to quantify the thermal reliability of TIMs during mechanical cycling using a custom-built steady-state thermal conductivity tester. Additionally, an optical technique was utilized to observe void formation, pump-out, and dry-out behavior during cycling, in order to correlate the thermal performance with physical behaviors of the TIM under cyclic stress. After an initial long-term static test, cyclic testing was found to degrade the thermal performance of the TIM through increasing its interfacial resistance. Optical qualitative measurements revealed the breakdown of the TIM structure at the interface, which indicated the formation of voids due to TIM degradation. Applying this testing method for future TIM development could help in optimizing TIM structure for particular package applications.