OBJECTIVE To evaluate and compare regulation of diabetes mellitus (DM) in dogs with cataracts and well-controlled DM that received an ophthalmic preparation of prednisolone acetate versus diclofenac sodium. ANIMALS 22 client-owned dogs with cataracts and well-controlled DM. PROCEDURES A prospective, randomized, double-masked, experimental study was conducted. On days 0 and 32, serum fructosamine concentrations (SFCs), clinical scores, and body weights were determined. Dogs were assigned to receive a topically administered ophthalmic preparation of either prednisolone acetate 1% or diclofenac sodium 0.1% in each eye 4 times daily for 28 days. Data analysis was conducted with generalized linear mixed models. RESULTS Findings indicated no meaningful differences in SFCs, clinical scores, or body weights between the treatment groups on days 0 or 32. Clinical score on day 0 was positively associated with SFC, as indicated by the corresponding rate of change such that each 1 -unit increase in clinical score was associated with an approximately 45.6 ± 9.4 μmol/L increase in SFC. In addition, the least squares mean ± SEM SFC was higher in spayed females (539.20 ± 19.23 μmol/L; n = 12) than in castrated males (458.83 ± 23.70 μmol/L; 8) but did not substantially differ between sexually intact males (446.27 ± 49.72 μmol/L; 2) and spayed females or castrated males regardless of the treatment group assigned. CONCLUSIONS AND CLINICAL RELEVANCE Findings indicated no evidence for any differential effect on DM regulation (assessed on the basis of SFCs, clinical scores, and body weights) in dogs treated topically with an ophthalmic preparation of prednisolone versus an ophthalmic preparation of diclofenac. Additional research investigating plasma concentrations of topically applied ophthalmic glucocorticoid medications is warranted.