Traumatic brain injury (TBI) causes complex, time-dependent molecular and cellular responses, which including adaptive changes that promote repair and recovery, as well as maladaptive processes such as chronic inflammation that contribute to chronic neurodegeneration and neurological dysfunction. Hormesis is a well-established biological phenomenon in which exposure to low-dose toxins or stressors results in protective responses to subsequent higher-level stressors or insults. Hormetic stimuli show a characteristic U-shaped or inverted J-shaped dose-response curve, as well as being time and exposure-frequency dependent, similar to pre-conditioning and post-conditioning actions. Voluntary exercise interventions, before or after injury, appear to follow these general hormetic principles. But the molecular alterations associated with exercise interventions or more general hermetic responses have received only limited attention. In this study we used a well-characterized mouse TBI model to assess the effects of different post-conditioning exercise-intervention paradigms on diverse molecular pathways, including neuroinflammation regulators, and post-traumatic neurological deficits. We generated high-throughput gene expression data and associated molecular pathway analyses to assess the potential molecular mechanisms associated with time and duration dependent, voluntary exercise intervention, as well as time after treatment. Importantly, we also utilized newer analytical methods to more broadly assess the impact of exercise on diverse molecular pathways. TBI caused long-term changes in multiple neuroinflammation markers and chronic cognitive dysfunction. Notably, all delayed, post-conditioning exercise interventions reduced posttraumatic neuroinflammation and/or attenuated the related cognitive changes, albeit with different pathway specificity and effects magnitude. Exercise comprehensively reversed injury-associated effects in the hippocampus across both activated inflammatory and inhibited neuronal pathways, consistent with a return toward the non-injured, homeostatic state. In contrast, the cortex showed a less consistent pattern with more limited attenuation of inflammatory pathway activation and an amplification in the injury-dependent inhibition of select non-inflammatory pathways, indicating less effective and potentially detrimental responses to exercise. Exercise intervention beginning two-weeks after injury and lasting two-weeks was less effective than exercise continuing for four-weeks. Exercise initiated at a more delayed timepoint of 6 weeks after injury and continuing for 4 weeks was more effective than during the acute phase. The delayed paradigm was also more effective than exercise initiated at ten-weeks after injury and continuing for eight-weeks, consistent with hormetic responses in other models and species. Overall, our study delineates regional and interventional parameters, as well as related molecular pathway changes, associated with post-conditioning exercise treatment, which may help inform future translational interventional strategies.