We developed a transgenic mouse strain expressing human C3 on the C57BL/6JGpt background to study C3 glomerulopathy (C3G), a group of kidney disorders driven by dysregulated alternative pathway complement activation. This model mirrors key aspects of C3G pathology seen in humans, including early-life morbidity, kidney, liver, and heart damage, renal anemia, and related pathological features. Dysregulation between human C3 and mouse complement proteins in these mice leads to spontaneous and severe disease progression resembling C3G. Treatment with a complement factor B inhibitor demonstrates therapeutic benefit, highlighting the model's relevance for testing complement-targeted therapies. Therefore, humanized C3 transgenic mice represent a valuable tool for evaluating drugs targeting complement pathway activation in C3G.