Background Evidence supporting the effectiveness of therapeutic protocols for nonassociative immune‐mediated hemolytic anemia (na‐IMHA) is weak. Hypothesis/Objectives Investigate the efficacy of various drugs in na‐IMHA. Animals Two hundred forty‐two dogs. Methods Multi‐institutional retrospective study (2015‐2020). Immunosuppressive effectiveness was determined by time to packed cell volume (PCV) stabilization and duration of hospitalization through analysis by mixed model linear regression. Occurrence of disease relapse, death, and antithrombotic effectiveness, were analyzed using mixed model logistic regression. Results Use of corticosteroids vs a multi‐agent protocol had no effect on time to PCV stabilization ( P = .55), duration of hospitalization ( P = .13), or case fatality ( P = .06). A higher rate of relapse ( P = .04; odds ratio: 3.97; 95% confidence interval [CI]: 1.06‐14.8) was detected in dogs receiving corticosteroids (11.3%) during follow‐up (median: 28.5 days, range: 0‐1631 days) compared to multiple agents (3.1%) during follow up (median: 47.0 days, range: 0‐1992 days). When comparing drug protocols, there was no effect on time to PCV stabilization ( P = .31), relapse ( P = .44), or case fatality ( P = .08). Duration of hospitalization was longer, by 1.8 days (95% CI: 0.39‐3.28 days), for the corticosteroid with mycophenolate mofetil group ( P = .01) compared to corticosteroids alone. Use of clopidogrel vs multiple agents had no effect on development of thromboses ( P ≥ .36). Conclusions and Clinical Importance Addition of a second immunosuppressive agent did not alter immediate outcome measures but might be associated with a reduction in relapse. Use of multiple antithrombotic agents did not reduce incidence of thrombosis.