Both adaptation and plasticity are critical for species persistence during rapid anthropogenic global change. However, we know little about how these mechanisms of resilience interact, particularly the role of epigenetic variation in long-term adaptation. We used a 25-generation selection experiment simulating future acidification, warming, and their combination to reveal how epigenetic and genetic mechanisms interact to promote resilience in a foundational copepod at the base of the marine food web. Epigenetic divergence was positively linked to gene expression divergence, indicating that epigenetic changes may facilitate phenotypic change. In contrast, genetic and epigenetic changes were negatively related, where genomic regions experiencing significant epigenetic changes had lower genetic divergence than those without. Thus, evolutionary and epigenetic changes acted in different regions of the genome during adaptation to global change conditions, due to either local inhibition of one another or distinct functional targets of selection. These results suggest that both genetic and epigenetic mechanisms underlie resilience to global change but have unique contributions.