Hyperoxaluria is characterized by an increased excretion of urinary oxalate which is caused by inherited disorders or high oxalate intake leading to renal stone ailment. Until date, reactive oxygen species and inflammation has been convicted for the progression of kidney stones for which antioxidant therapy has been employed. However, recent studies have linked the association of endoplasmic reticulum stress and oxidative imbalance in the progression of renal diseases. Considering oxidative stress being at forefront in causing hyperoxaluric consequences, current study was designed to correlate the impact of hyperoxaluria and regulation of oxidative imbalance via inhibition of endoplasmic reticulum stress by 4-phenylbutyric acid (4-PBA). Male wistar rats were subdivided into three groups, i.e., normal control (C), hyperoxaluric rats given ethylene glycol (EG), and hyperoxaluric rats treated with 4-PBA (EG + PBA). After 28 days of treatment, assessment of antioxidant defence system, inflammation, ER stress, and subsequent unfolded protein response was studied in renal tissue. It was found that the hyperoxaluric insult led to a marked damage to the renal tissue resulting in compromised antioxidant levels, upregulation of ER stress markers along with a steep surge in the extent of inflammation. However, 4-PBA treatment significantly curtailed the deleterious effects of hyperoxaluria by lowering down the level of stress markers as well as normalizing the antioxidant defence enzymes. Therefore, chemical chaperones can be deemed as a new class of drugs for the treatment of hyperoxaluric induced renal damage.