Introduction: The hemodynamic demands on the heart during normal pregnancy induce physiological cardiac hypertrophy. Together with exercise induced cardiac hypertrophy and cardiac enlargement during post-natal growth, these physiological cardiac adaptations are distinct from pathological hypertrophy caused by heart diseases including volume/pressure overload. Exercise-induced cardiac hypertrophy can induce a protective phenotype that leads to resistance from ischemic injury or pressure overload induced pathological remodeling. Whether pregnancy induced cardiac hypertrophy can also protect the heart from post-partum (PP) pathological stimuli remains unknown and is the focus of this study. Methods: We challenged both post-partum and age matched non-pregnant female C57BL/6 mice with 7-day osmotic minipump infusion of Angiotensin II/phenylephrine (AngII/PE) and determined the cardiac alterations. Results: PP mice had more severe cardiac pathological remodeling after AngII/PE infusion compared with non-pregnant counterparts, with greater increases in heart weight, cardiomyocyte hypertrophy and fibrosis. Echocardiography showed both left and right ventricular hypertrophy without overt systolic dysfunction. PP mice had greater elevations in expression levels of fetal genes and fibrotic genes compared with non-pregnant mice after AngII/PE infusion. RNA-sequencing analysis suggested a more robust change in gene expression level in PP mice after AngII/PE treatment compared to non-pregnant counterparts, with a substantial role for extracellular matrix organization genes. We also found a significant alteration of gene expression levels for enriched extracellular structural organization at 1-day PP, which underlies ongoing structural re-organization in the myocardium shortly after deliver. These PP changes may predispose the heart to adverse remodeling when simultaneously challenged with pathological stimuli. Conclusions: Pregnancy induced cardiac remodeling does not protect the heart against PP pathological stimuli. In fact, the rapid remodeling in the PP heart may predispose it to exacerbation of pathological remodeling.