A core thesis of cognitive neurogenetic research is that genetic effects on cognitive ability are mediated by specific neural functions, however, demonstrating neural mediation has proved elusive. Pairwise relationships between genetic variation and brain function have yielded heterogeneous findings to date. This heterogeneity indicates that a multiple mediator modeling approach may be useful to account for complex relationships involving function at multiple brain regions. This is relevant not only for characterizing healthy cognition but for modeling the complex neural pathways by which disease-related genetic effects are transmitted to disordered cognitive phenotypes in psychiatric illness. Here, in 160 genotyped functional magnetic resonance imaging participants, we used a multiple mediator model to test a gene-brain-cognition pathway by which activity in 4 prefrontal brain regions mediates the effects of catechol-O-methyltransferase (COMT) gene on cognitive control and IQ. Results provide evidence for gene-brain-cognition mediation and help delineate a pathway by which gene expression contributes to intelligence.