As a consequence, our present exploration revealed that melatonin could ameliorate renal FMT and renal fibrosis via miR‐21‐5p/PTEN and/or miR‐21‐5p/Spry1 signalling pathway, which may be a vital anti‐fibrotic mechanism of melatonin. The gene discussed is PTEN; the disease is renal fibrosis.