Aims and background: A great saphenous vein (GSV) is a significant superficial vein of the lower limb, frequently utilized for various medical procedures including venous access, vascular surgeries, and grafting. This systematic review aims to comprehensively analyze the research articles on anatomical variations of the human GSV, including its course, termination, size, and relationship with surrounding structures. The primary outcome of this review was the anatomical variation of the GSV at different regions of the lower limb. Materials and methods: The search was conducted through November 2023, utilizing the electronic databases PubMed, Cochrane Library, ScienceDirect, Google Scholar, SciELO, and manual searches of reference lists for articles published between 2005 and 2023. The number of articles reviewed was 10. Results: Most of the studies were performed by venous ultrasound (41.96%) and computed tomography venography (39.43%), while other studies used dissection (9.5%). One study was conducted postmortem (4.2%), and another utilized histological examination (2.04%). Conclusion: Most commonly, the GSV is located medially, and true duplication of the GSV was identified as an infrequent occurrence in only 1% of cases. Complications with the saphenous veins, as well as other leg veins, can give rise to an array of distressing symptoms. Clinical significance: The review will also explore the clinical significance of these variations, such as their impact on surgical procedures, ultrasound-guided interventions, and clinical assessments. Phlebography remains an indispensable tool for detecting and diagnosing complex venous conditions.