The impact of ocean acidification on marine ecosystems will depend on species capacity to adapt1,2. Recent studies show that the behaviour of reef fishes is impaired at projected CO2 levels3,4; however, individual variation exists that might promote adaptation. Here, we show a clear signature of parental sensitivity to high CO2 in the brain molecular phenotype of juvenile spiny damselfish, Acanthochromis polyacanthus, primarily driven by circadian rhythm genes. Offspring of CO2-tolerant and CO2-sensitive parents were reared at near-future CO2 (754 μatm) or present-day control levels (414 μatm). By integrating 33 brain transcriptomes and proteomes with a de novo assembled genome we investigate the molecular responses of the fish brain to increased CO2 and the expression of parental tolerance to high CO2 in the offspring molecular phenotype. Exposure to high CO2 resulted in differential regulation of 173 and 62 genes and 109 and 68 proteins in the tolerant and sensitive groups, respectively. Importantly, the majority of differences between offspring of tolerant and sensitive parents occurred in high CO2 conditions. This transgenerational molecular signature suggests that individual variation in CO2 sensitivity could facilitate adaptation of fish populations to ocean acidification.