Vancomycin is a potent antibiotic against Gram‐positive bacteria; however, its use can be limited by nephrotoxicity. Several reports showed that proton pump inhibitors (PPIs) are associated with renal impairment. Many hospitalized patients are prescribed both drugs. As the literature lacks data on the potential augmentation of acute kidney injury (AKI) risk with this combination, we aimed to assess such risk. This was a retrospective cohort study of hospitalized patients receiving either VAN‐PPI or VAN alone for ≥72 h. Patients with a baseline serum creatinine (SCr) of ≥1.5 mg/dL were excluded. AKI incidence was assessed 3–5 days post VAN‐PPI or VAN initiation. Of 300 patients, 186 were in the VAN‐PPI group and 114 in the VAN group. The percentage of patients meeting AKI definition was not different between the two groups (11.8% vs. 7.9%; P = 0.277); however, the percentage change in SCr on Days 3–5 was only numerically higher in the VAN‐PPI group (1% vs. −2.4%; P = 0.242). The distribution of patients meeting different RIFLE class criteria was not different (P = 0.320). Using VAN with PPI was not associated with augmented AKI risk. However, monitoring kidney function would still be recommended as a standard good clinical practice when either drug is used.