Abstract Background and Hypothesis Thrombotic microangiopathy (TMA) is increasingly recognized as a complication of both cancer and anti-cancer therapies. C5 complement inhibition is used in selected cases, but evidence supporting its effectiveness, particularly in kidney biopsy-proven disease, remains limited. Methods This retrospective cohort study included adult patients with biopsy-proven TMA attributed to anti-cancer therapies between 2015 and 2026 at Mayo Clinic, USA. Patients were stratified according to treatment with complement inhibition versus no complement inhibition therapy. The primary outcome was renal recovery; secondary outcomes included hematological recovery, composite outcome, overall survival, and longitudinal changes in hematologic and renal function parameters. Results A total of 31 patients with kidney biopsy-proven TMA related to anti-cancer therapy were included. Nine received complement inhibition, and 22 did not. A higher proportion of patients in the treated group achieved complete or partial renal recovery at 3 months (p = 0.008), hematologic recovery at 1 month (p = 0.007) and composite outcome (complete-partial renal plus hematologic recovery) (p = 0.041). During follow-up, platelet counts increased significantly at 1 month and 3 months (p = 0.045, both) in the treated group. Mixed-effects modeling showed significantly lower longitudinal estimated glomerular filtration rate (eGFR) values in the untreated group (β = −13.9 mL/min per 1.73 m², p = 0.028). In the gemcitabine-associated TMA subgroup, complete-partial renal recovery occurred only in treated patients (p = 0.021) and hematologic recovery was achieved in the whole cohort but occurred significantly faster in the complement inhibition group (p = 0.019). The higher rate of renal recovery persisted in sensitivity analysis (p = 0.021). Conclusions In this rigorously phenotyped cohort of patients with biopsy-proven, anti-cancer therapy-associated renal TMA, we observed a signal of benefit from C5 inhibition, most consistently for renal recovery and possibly extending to hematologic outcomes, particularly among patients with gemcitabine-associated TMA.