The metabolic syndrome (MetS) and chronic kidney disease are global health issues. The MetS induces hypertension (HTN) and commonly results in renal damage. The optimal therapy for HTN in the MetS is unknown. Thiazide diuretics are first line therapy; however, these drugs may have untoward effects. This study investigated the effects of azilsartan (AZL), chlorthalidone (CLTD), and the combination (AZL + CLTD) on blood pressure and renal injury in a rodent model with features of the MetS. Dahl salt‐sensitive (Dahl S) rats were fed high‐fat (36% fat) high‐salt (4% NaCl) diet. Groups were then treated with vehicle, AZL (3 mg/kg/day), CLTD (5 mg/kg/day) or AZL+CLTD. Mean arterial pressure (MAP) was recorded continuously by telemetry. After 26 days, rats were humanely killed and kidneys were harvested for histology. Both AZL and CLTD attenuated the rise in blood pressure compared to vehicle, and the combination further reduced blood pressure compared to CLTD alone. All treatments reduced proteinuria and albuminuria. Only groups treated with AZL prevented nephrinuria. Nephrinuria was 57% lower, and proteinuria was 47% lower with combination therapy compared to AZL alone. All treatments reduced the number of inflammatory cells in the kidney. In conclusion, in our model, AZL and CLTD lower blood pressure and exhibit renal protective effects. AZL treatment offers additional protection as evidenced by lower nephrinuria and plasma MCP‐1. Combination therapy afforded the greatest protective effects and may be the best choice for hypertensive therapy in the MetS. This article is protected by copyright. All rights reserved.