Acute kidney Injury (AKI) is a common medical emergency that often occurs after an ischemia event followed by reperfusion. Matrix metalloproteinases (MMP-2) and MMP-9 are turned up in ischemia-reperfusion injury (IRI), which destroys the microvascular matrix of the kidney and causes ischemic organ damage. Further, histone deacetylase-2 (HDAC-2) is the major regulator of key signalling mechanisms in IRI. Alpha-cyperone (CYP), with its anti-inflammatory and antioxidant properties, might be a useful therapeutic strategy for kidney preservation. We employed an IRI model of the kidney to look at the expression of MMP-2, MMP-9, and HDAC-2, as well as the possible protective effect of cyperone treatment before IRI on metallozymes expression and IRI-induced renal damage. Male Wistar albino rats were selected at random and divided into three groups: sham-operated, ischemia-reperfusion, and cyperone-pretreated. The IRI model was produced by unilaterally clamping the renal artery for 45 minutes and reperfusion for 24 hours. Blood was collected for measuring serum creatinine, blood urea nitrogen (BUN), uric acid, and expression of MMPs and HDAC-2 in the renal homogenate. The effects of cyperone on the expression of MMPs and HDAC-2 in the kidney were investigated by enzyme-linked immunosorbent assay. The histopathological examinations were performed to score tubular damage and fibrosis by light microscopy. Increased expression of MMP-2, MMP-9, and HDAC-2 was seen in renal IRI. One week of pre-treatment with CYP (50 mg/kg p.o.) was sufficient to reverse these modifications. Preventive CYP treatment before renal ischemia improved renal parameters, malondialdehyde, myeloperoxidase, hydroxyproline, and pathological damage compared to control. Our results suggest that CYP pretreatment may reduce the effects of IRI induced oxidative stress, pro-inflammatory factors, and fibrosis by reducing the production of MMP-2, MMP-9, and HDAC-2. More research is needed to understand how CYP and metalloenzymes interact in AKI.