Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury, particularly in diabetic patients. Previous studies have shown renoprotective effects of glucagon-like peptide-1 (GLP-1) signalling; however, its role in CIN remains unexplored. This study investigates the prophylactic effect of exendin-4, a GLP-1R agonist, against CIN in a rat model mimicking both healthy and diabetic conditions. Animals were randomly divided into 7 groups: a control sham group (n = 8), and 2 identical sets of 3 disease groups, one received exendin-4 before exposure to contrast medium (CM), while the other served as untreated control. The 3 disease groups represented diabetes (n = 8), CIN (n = 8), or diabetes and CIN combined (n = 8). Untreated groups showed deteriorating renal function as indicated by significantly higher levels of serum creatinine and blood urea nitrogen, malondialdehyde, and endothelin-1 and caspase-3 expression compared to the sham control group. This was accompanied by a significant decrease in tissue reserves of reduced glutathione, superoxide dismutase, nitrate and endothelin nitric oxide synthase as well as deteriorating renal histology. The CM-induced changes in diabetic rats indicate impaired renal function, oxidative stress, vascular dysfunction, and apoptosis, and were significance higher in intensity compared to non-diabetic rats. Pretreatment with exendin-4 ameliorated all the aforementioned CM-induced nephropathic effects independent of the glycemic state. To our knowledge, this is the first study describing the prophylactic renoprotective effects of exendin-4 against CIN. With the current pharmaceutical use of exendin-4 as a hypoglycaemic agent, the GLP-1R agonist becomes an interesting candidate for human clinical trials on CIN prevention.