Methotrexate (MTX) stands as a noteworthy example of a potent anticancer and anti-rheumatic drug that has gained approval from the FDA for its efficacious treatment of various cancer types and non-oncologic diseases such as rheumatoid arthritis and psoriasis. Its remarkable ability to inhibit cellular proliferation by curtailing the synthesis of purine and pyrimidine has solidified its place in the medical field. Nonetheless, the panorama is not devoid of challenges, with the clinical utilization of MTX being somewhat constrained due to an array of associated toxicities, most prominently nephrotoxicity—an adversity that can be both devastating and unfortunately common. The challenges associated with MTX nephrotoxicity arise due to its significant dependence on renal excretion for clearance, making the kidneys highly vulnerable to its effects. The objective of this review is to elucidate the potential mechanisms underlying MTX-induced nephrotoxicity and to discuss promising phytochemical protective strategies investigated experimentally within the past two years. This exploration aims to provide a comprehensive understanding of the challenges associated with MTX usage, particularly its impact on renal function, and to highlight emerging strategies for mitigating nephrotoxic effects.