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3‐Monochloropropane‐1,2‐diol (3‐MCPD) as a byproduct of food processing and a carcinogenic agent has attracted much attention in the last decades. Kidney is the main target organ that is sensitive to the toxicity of 3‐MCPD. Due to limited evidence about possible 3‐MCPD toxicity, we design an investigation to determine the role of mitochondrial biogenesis following chronic oral administration of 3‐MCPD (2, 4, 8 and 32 mg/kg) for 2 months in male C57 mice. The present study evaluated the affects of 3‐MCPD in modulating metabolic signalling which is associated with Il‐18, PGC‐1α, Nrf‐2 and Sir3 which are the major transcription factors. Our data confirms controversial behaviors after chronic exposure with 3‐MCPD. Over expression of the PGC‐1α and Sir3 and IL‐18 were observed after exposure with 2,4 & 8 mg kg−1 day−1 of 3‐MCPD. In front, PGC‐1α down‐regulation occurs at the highest dose (32 mg/kg) resulted in kidney injury. Based on the findings, PGC‐1α plays an important role in the restoration of the mitochondrial function during the recovery from chronic kidney injury. We suggest that the PGC‐1α can be consider as a therapeutic target in prevention and treatment of kidney injury after chronic exposure of 3‐MCPD. Practical applications: 3‐Monochloropropane‐1, 2‐diol (3‐MCPD) existed in several foods, can induce nephrotoxicity, progressive nephropathy and renal tubule dilation following acute and chronic exposure. It revealed that 3‐MCPD toxicity is related to metabolites which can cause oxidative stress and activation of cell death signaling. It seems that cytotoxicity of 3‐MCPD has disruptive effect on kidney cells due to rise in ROS production and decrease in mitochondrial membrane permeability. These effects can lead to MPT pore opening, cytochrome c release and activation of programed cell death signaling pathway. Therefore, present study was investigated the role of PGC‐1a and the metabolic signaling involved in 3‐MCPD‐induced nephrotoxicity for the first time. Our data revealed that up‐regulation of mitochondrial biogenesis following chronic exposure with 3‐MCPD accelerates recovery of mitochondrial and cellular function in kidney by deacetylation of histones, overexpression of transcription factors (PGC‐1α, Nrf‐2, and Sir3) and maintaining cellular homeostasis. [ABSTRACT FROM AUTHOR]