Sympathoexcitation is a hallmark of heart failure, with sustained β-adrenergic receptor (βAR)-G protein signaling activation. βAR signaling is modulated by regulator of G protein signaling (RGS) proteins. Previously, we reported that Gαi/o regulation by RGS2 or RGS5 is key to ventricular rhythm regulation, while the dual loss of both RGS proteins results in left ventricular (LV) dilatation and dysfunction. Here, we tested whether sustained βAR stimulation with isoproterenol (ISO, 30 mg/kg/day, 3 days) exacerbates LV remodeling in male mice with germline deletion of Rgs2 and/or Rgs5. Rgs2 KO and Rgs2/5 dbKO mice showed LV dilatation at baseline, which was unchanged by ISO. Rgs2 or Rgs5 deletion decreased Rgs1 expression, whereas Rgs5 deletion increased Rgs4 expression. ISO induced cardiac hypertrophy and interstitial fibrosis in Rgs2/5 dbKO mice without increasing cardiomyocyte size or LV dilation but increased expression of cardiac fetal gene Nppa, α-actinin, and Ca2+-/calmodulin-dependent kinase II. Single Rgs2 and Rgs5 KO mice had markedly increased CD45+ cells, whereas tissue from Rgs5 KO mice showed increased CD68+ cells, as revealed by immunohistochemistry. The results together indicate that ventricular remodeling due to Rgs2 and/or Rgs5 deletion is associated with augmented myocardial immune cell presence but is not exacerbated by sustained βAR stimulation.