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In cardiac fibroblasts, angiotensin II (Ang II) can increase connexin 43 (Cx43) expression and promote calmodulin-dependent protein kinase II (CaMKII) activation. Cx43 overexpression is crucial for the fibroblast-myofibroblast transition. The main purpose of the present study was to investigate the role of CaMKII in regulating Cx43 expression and to determine whether the CaMKII/Cx43 pathway is essential for controlling fibroblast activation and differentiation. In vivo, 4 weeks of Ang II infusion enhanced CaMKII activation but reduced Cx43 expression in hearts undergoing fibrosis remodeling, while in cultured neonatal rat fibroblasts, CaMKII activation upregulated Cx43 expression via transforming growth factor-beta1 (TGF-β1). CaMKII inhibition by Ang-(1-7) or auto-camtide 2-related inhibitory peptide reversed the Ang ll-induced changes in Cx43 expression and attenuated Ang ll-induced upregulation of alpha smooth muscle actin and TGF-β1 in both Ang ll-infused rats and cultured fibroblasts. Based on the in vivo and in vitro experimental results, CaMKII plays a pivotal role in the Ang II-mediated fibroblast-myofibroblast transition by modulating the expressions of TGF-β1 and Cx43. We conclude that Ang II mediates the fibroblast-myofibroblast transition partially via the Ang Il/CaMKll/TGF-β1/Cx43 signaling pathway.