Background and objective Cardiac-directed adenylyl cyclase 6 (AC6) expression attenuates left ventricular (LV) hypertrophy and dysfunction in cardiomyopathy, but its effects in the pressure-overloaded heart are unknown. Methods Mice with cardiac-directed and regulated expression of AC6 underwent transaortic constriction (TAC) to induce LV pressure overload. Ten days prior to TAC, and for the duration of the 4 week study, cardiac myocyte AC6 expression was activated in one group (AC-On) but not the other (AC-Off). Multiple measures of LV systolic and diastolic function were obtained 4 week after TAC, and LV samples assessed for alterations in Ca 2+ signaling. Results LV contractility, as reflected in the end-systolic pressure–volume relationship ( E max), was increased ( p = 0.01) by activation of AC6 expression. In addition, diastolic function was improved ( p < 0.05) and LV dilation was reduced ( p < 0.05). LV samples from AC-On mice showed reduced protein expression of sodium/calcium exchanger (NCX1) ( p < 0.05), protein phosphatase 1 (PP1) ( p < 0.01), and increased phosphorylation of phospholamban (PLN) at Ser16 ( p < 0.05). Finally, sarcoplasmic reticulum (SR) Ca 2+ content was increased in cardiac myocytes isolated from AC-On mice ( p < 0.05). Conclusions Activation of cardiac AC6 expression improves function of the pressure-overloaded and failing heart. The predominant mechanism for this favorable adaptation is improved Ca 2+ handling, a consequence of increased PLN phosphorylation, reduced NCX1, reduced PP1 expression, and increased SR Ca 2+ content.