Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We conducted this first-in-human, phase I clinical trial to determine the safety, tolerability, and pharmacokinetic (PK) (including food effect) profiles of mefunidone administered orally as single and multiple ascending doses in healthy subjects. Part A assessed single ascending doses of mefunidone from 25mg to 800mg or placebo once daily in the fasting state. Part A also assessed the effect of food on tolerability and PK in the 100mg cohort. Part B consisted of three treatment groups who received 100mg, 200mg, or 400mg of mefunidone or placebo twice daily (BID, bis in die) on days 1-6 and once in the morning on day 7. Single oral doses of mefunidone up to 800mg and multiple doses of mefunidone up to 400mg BID were all well-tolerated. Mefunidone behaved with ideal dose proportionality within the single-dose range of 50mg-600mg and the multiple-dose range of 100mg BID to 400mg BID by day 7. High-fat fed conditions led to a delay in Tmax by approximately 1h and a slight reduction of approximately 20% in Cmax compared to that in fasting conditions, but it did not significantly affect systemic exposure. Mefunidone exhibited favorable pharmacokinetics and safety profiles. The present study informed and supported further developmental clinical studies of mefunidone. clinicaltrials.gov, identifier CXHL1900206.