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Eluxadoline is approved for the treatment of diarrhea‐predominant irritable bowel syndrome in the United States. The impact of renal impairment on the pharmacokinetic (PK) parameters of eluxadoline is currently unknown. This phase 1, open‐label, parallel‐group study evaluated the PK and safety profile of eluxadoline in 8 participants with renal impairment and 8 matched healthy controls. Of the participants with renal impairment, 2 had severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and 6 had end‐stage renal disease while not yet on dialysis (eGFR <15 mL/min/1.73 m2). The primary objective was to assess plasma and urine PKs, and plasma protein binding of eluxadoline. In participants with renal impairment, mean plasma concentrations of eluxadoline were consistently higher compared with matched healthy controls: 1.4‐fold higher for mean maximum plasma concentration (Cmax) and 2.2‐fold higher for mean area under the plasma concentration‐time curve from time 0 to time t. The median time to Cmax was 2.5 hours in both groups. Although eluxadoline is a locally acting drug with low oral bioavailability, because of the increased systemic exposure in participants with renal impairment as a cautionary measure the lower approved dose of 75 mg twice daily is recommended for individuals with severe renal impairment and end‐stage renal disease while not yet on dialysis. Eluxadoline 100 mg single dose was well tolerated in participants with renal impairment and matched healthy controls. [ABSTRACT FROM AUTHOR]