Recovery following muscle-damaging downhill running is associated with increased muscle inflammatory cytokines. Various inflammatory challenges can also increase cytokines in the brain, which have been linked to sickness behaviors, including fatigue, but little is known about the brain cytokine response to stressful exercise. We used a downhill running model to determine the relationship between brain IL-1beta and recovery of running performance. Male C57BL/6 mice were assigned to: downhill (DH), uphill (UH), or non-running control (Con) groups and run on a treadmill at 22 m/min and -14% or 14% grade, for 150 min. Following the run, a subset of DH and UH was placed into activity wheel cages where voluntary running activity was measured for 7 days. A second subset was run to fatigue on a motorized treadmill at 36 m/min, 8% grade at 24, 48, and 96 h post-up/downhill run. A third subset of DH, UH, and Con mice had brains dissected and assayed for IL-1beta at 24 and 48 h. DH resulted in delayed recovery of both voluntary wheel-running and treadmill running to fatigue as compared to UH (p < .05). DH was also associated with increased IL-1beta concentrations in cortex (at 24 and 48 h) and cerebellum (24 h) as compared to UH and Con. UH was not different than Con in any brain region. Eccentric-biased downhill running results in an increase in plasma CK and delayed recovery in running performance, as compared to the more metabolically demanding uphill running, and this was associated with increased concentrations of IL-1beta in regions of the brain responsible for movement, coordination, motivation, perception of effort, and pain.