Background: to evaluate the effects of one week of supplementation with curcumin combined with piperine on physical performance, immune system cell counts, muscle damage, and plasma levels of inflammatory markers after a treadmill running training session. Methods: This study is a double-blind, crossover-balanced clinical trial with a three-week intervention. Sixteen male runners with a mean age of 36 ± 9 years and VO2 max of 60.6 ± 9.03 mL.kg −1 min −1 were recruited and randomly divided into 2 groups: the first group (CPG) was supplemented daily for 7 days with 500 mg of curcumin + 20 mg piperine, and the second group (PG) was supplemented with 540 mg of cellulose. After the 7th day of supplementation, the volunteers participated in the experimental running protocol, where blood samples were collected before, after, and one hour after exercise for analysis of the number of leukocytes, creatine kinase, and cytokine concentration (IL-2, TNF-α, IFN, IL-6, and IL-10) using flow cytometry. This process was repeated, reversing the supplementation offered to the groups. Results: curcumin and piperine supplementation could not change the physical performance, immune cell counts, and muscle damage; however, the aerobic fatiguing exercise protocol inhibited the elevation of the plasmatic levels of some cytokines. The running exercise protocol could elevate the circulating levels of IL-2 (from 49.7 to 59.3 pg/mL), TNF-α (from 48.5 to 51.5 pg/mL), INF (from 128.8 to 165.0 pg/mL), IL-6 (from 63.1 to 77.3 pg/mL), and IL-10 (from 48.9 to 59.6 pg/mL) 1 h after the end of the running protocol. However, the curcumin and piperine supplementation could inhibit this elevation. Conclusions: curcumin and piperine supplementation had no effect on physical performance, immune cell counts, or muscle damage; however, the supplementation could modulate the kinetics of IL-2, TNF-α, INF, IL-6, and IL-10 1 h after the end of exercise.