The objective of this study was to evaluate whether there is an interaction between pepper extract (PE) supplementation and evaporative cooling regimens on the performance, thermal comfort, and metabolism of lactating cows. The experiment was designed as a double 4 × 4 Latin square using eight multiparous Holstein cows (days in milk 147 ± 43.8 days). Treatments were a 2 × 2 factorial arrangement; two evaporative cooling regimens [sprinkler cycles of 30 s on and 4.5 min off (R5) and 30 s on and 9.5 min off (R10)] were combined with no inclusion of pepper extract (CT) or 800 mg/cow daily of PE. The inclusion of PE allowed a greater reduction in the surface temperature of the coat, and the cows remained for longer periods in the feeding area. There was an interaction between the use of PE and the climate regimen for surface temperature, which was lower for PER5. Cows experiencing greater intermittency in the spraying cycles (R10) spent 35% more time at the feeding area. A significant interaction was observed for milk production, with greater production for CTR5 compared to the other treatments. The feed efficiency for R5 was higher than that for R10. The R5 treatment combined with PE reduced water intake. There was no significant difference in serum parameters other than gamma-glutamyl transferase, with an interaction between treatments and greater activity for PER10, and total protein and albumin, which had cooling effects that were higher for R10. The two factors tested interfered in different and dissociated ways. The evaporative cooling strategies were effective, and the R5 treatment resulted in higher feed efficiency and milk production. The inclusion of PE enhanced heat reduction in cows when they were subjected to a cooling regime.