First-generation calcium channel blockers such as verapamil are a widely used class of antihypertensive drugs that block L-type calcium channels. We recently discovered that they also reduce cardiac expression of proapoptotic thioredoxin-interacting protein (TXNIP), suggesting that they may have unappreciated transcriptional effects. By use of TXNIP promoter deletion and mutation studies, we found that a CCAAT element was mediating verapamil-induced transcriptional repression and identified nuclear factor Y (NFY) to be the responsible transcription factor as assessed by overexpression/knockdown and luciferase and chromatin immunoprecipitation assays in cardiomyocytes and in vivo in diabetic mice receiving oral verapamil. We further discovered that increased NFY-DNA binding was associated with histone H4 deacetylation and transcriptional repression and mediated by inhibition of calcineurin signaling. It is noteworthy that the transcriptional control conferred by this newly identified verapamil-calcineurin-NFY signaling cascade was not limited to TXNIP, suggesting that it may modulate the expression of other NFY targets. Thus, verapamil induces a calcineurin-NFY signaling pathway that controls cardiac gene transcription and apoptosis and thereby may affect cardiac biology in previously unrecognized ways.