SignificanceParental health and diet at the time of conception determine the development and life-long disease risk of their offspring. While the association between poor maternal diet and offspring health is well established, the underlying mechanisms linking paternal diet with offspring health are poorly defined. Possible programming pathways include changes in testicular and sperm epigenetic regulation and status, seminal plasma composition, and maternal reproductive tract responses regulating early embryo development. In this study, we demonstrate that paternal low-protein diet induces sperm-DNA hypomethylation in conjunction with blunted female reproductive tract embryotrophic, immunological, and vascular remodeling responses. Furthermore, we identify sperm- and seminal plasma-specific programming effects of paternal diet with elevated offspring adiposity, metabolic dysfunction, and altered gut microbiota.