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Risk for heart disease increases with advanced age and differs between sexes, with females generally protected from heart disease until menopause. Despite these epidemiological and clinical observations, however, the molecular mechanisms of the cardiac aging life‐course and how it differs between sexes is not fully described. We used high throughput transcriptomics in juvenile (5 weeks), adult (4‐6 months), and aged (18 months) to understand how cardiac gene expression changes across the life‐course and by sex. Age‐related changes in cardiac gene expression differed significantly between males and females. While male gene expression changed from the juvenile‐adult and juvenile‐aged period (203 and 395 genes, respectively), adult‐old gene expression was unchanged. Female gene expression changed across the life‐course with 2009 genes from juvenile‐adult and 1656 from adult‐aged. Gene enrichment analysis of differentially expressed genes (DEG) suggests that juvenile to adulthood genes are clustered in cell‐cycle and development‐related pathways in contrast to adulthood to aged shift with immune and inflammation‐related pathways. Within age, significant sex differences existed as well. Juvenile and aged male and female mice displayed significantly different gene expression, while adult male and female gene expression was similar. Interestingly, there was very little overlap in differently expressed genes juvenile and aged mice, suggesting sex differences in early age are distinct from those in advanced age. Gene enrichment analysis shows early juvenile DEGs clustering in cell‐differentiation and development pathways, aged mice DEGs clustering in protein metabolism and its regulation, and suppression of some immune response pathways. These findings are contrary to expected sex differences historically attributed to estrogen, given that juvenile female mice are not yet sexually mature and the aged female cohort demonstrates cessation of estrous cycle. Thus, we suggest that mechanisms beyond sex hormones likely explain these significant sex‐specific differences across the mouse life‐course. Together, distinct trajectories in transcriptomic profile hints to fundamental age‐sex‐differences in cardiac aging and demonstrates the need for consideration of age and sex as biological variables in heart disease.