C3 glomerulopathy refers to renal disorders characterised by abnormal accumulation of C3 within the kidney, commonly along the glomerular basement membrane (GBM). C3 glomerulopathy is associated with complement alternative pathway dysregulation, which include functional defects in complement regulator factor H (FH). There is no effective treatment for C3 glomerulopathy. We investigated the efficacy of CR2-FH, a recombinant mouse protein comprised of domains from complement receptor 2 (CR2) and FH, in two models of C3 glomerulopathy, where there is either pre-existing or triggered C3 deposition along the GBM. FH-deficient mice spontaneously develop renal pathology associated with abnormal C3 accumulation along the GBM and secondary plasma C3 deficiency. CR2-FH partially restored plasma C3 levels in FH-deficient mice two hours after intravenous injection. CR2-FH specifically targeted glomerular C3 deposits, reduced the linear C3 reactivity assessed with anti-C3 and anti-C3b/iC3b/C3c antibodies and prevented further spontaneous accumulation of C3 fragments along the GBM. Reduction in glomerular C3d and C9/C5b-9 reactivity was seen after daily administration of CR2-FH for one week. In a second mouse model, utilising animals with combined deficiency of FH and complement factor I, CR2-FH prevented de novo C3 deposition along the GBM. These data showed that CR2-FH protected the GBM from both spontaneous and triggered C3 deposition in vivo and indicate that this approach should be tested in C3 glomerulopathy.