Introduction: Liver injury can result from various causes, including alcohol consumption, viral infections (such as hepatitis), autoimmune diseases, metabolic disorders, and exposure to certain chemicals, drugs or toxins. It can manifest as inflammation, fatty liver disease, cirrhosis, or acute liver failure, depending on the cause and severity. Treatment often involves addressing the underlying cause, lifestyle changes (such as avoiding alcohol or certain medications), and sometimes medication to support liver function or manage specific conditions. Early detection and management are crucial for preventing further damage and promoting liver health. Studies have reported the effects of Momordica balsamina on liver injury. Aim: This study aim to evaluate the prophylactic effect of methanolic leaf extract of Momordica balsamina against CCL4-induced liver injury in Wistar Rats. Methodology: The fresh leaves of Momordica balsamina were purchased at Marina Market, Sokoto, the plant was air dry at room temperature for 2 weeks and the air-dried leaves were processed with methanol to obtain methanolic extract. An acute toxicity study of M. balsamina extract was conducted with six doses (10, 100, 1000, 1600, 2900 and 5000 mg/kg) to evaluate its safety. Phytochemical analysis of the extract was carried out to detect the presence or absence of carbohydrates, saponins, flavonoids, tannins, phenols, protein, alkaloids, cardiac glycosides and steroids. A total of 42 Wistar rats (170±20g) of either sex roughly of the same age (8-10 weeks) were used for the study. After two weeks of acclimatization, the rats were randomly divided into six groups of seven rats each; group 1 (normal control) treated with distilled water and vital feeds; groups 2 (Negative control) CCl4 treated with liver injury not on treatment; group 3 (Standard control) CCl4 liver injury treated with 50 mg/kg Silymarin; group 4 (500 mg/kg M. balsamina + 2mL CCl4); group 5 (1000 mg/kg M. balsamina + 2mL CCl4) and group 6 (1500 mg/kg M. balsamina + 2mL CCl4) for 4 weeks. On the last day, the rats were anaesthetized, and blood and liver organ were collected for biochemical and histomorphology study. Results: The prophylactic effects of methanolic leaf extract of Momordica balsamina against CCl4-induced liver injury were evaluated on liver function tests (LFTs) and Malondialdehyde (MDA). This study shows that Momordica balsamina extract significantly (P< 0.05) decreased the level of serum AST, ALT, ALP, TB and DB positively by inhibiting their raise at dose-dependent manner compared to the negative control, equally, the extract increased the serum level of Albumin and total protein when compared to the negative control. On the other hand, the extract shows significant reduction of serum level of Malondialdehyde (MDA) near to normal at varying dose. The finding of the prophylactic effect of methanolic leaf extract of Momordica balsamina on histology shows significant improvement on liver cell with notable recovery and appearance of the histological architecture of the hepatocyte at the highest dose (1500 mg/kg+2mL CCl4) compared to negative control group. Conclusion: The presence of phytochemical compounds and antioxidant properties as well as a gene that is responsible for its prophylactic effect may be one of the mechanisms through which the plant extract was able to exert prophylactic effect on CCl4 induced liver injury in Wistar rats. This study suggests that M. balsamina extract may be considered as an affordable and non-invasive treatment option for liver injury in human.