Background: Severe open lower limb injuries, particularly Gustilo–Anderson Grade IIIB and IIIC fractures, pose a major challenge in trauma surgery due to the critical decision between limb salvage and amputation. The Mangled Extremity Severity Score (MESS) is widely used, while the Ganga Hospital Open Injury Severity Score (GHOISS) was developed to better address complex open fractures, especially in settings with advanced reconstructive capabilities. Aim and Objectives: To compare the effectiveness of the Mangled Extremity Severity Score (MESS) and the Ganga Hospital Open Injury Severity Score (GHOISS) in predicting limb salvage and guiding management decisions in modified Gustilo–Anderson Grade III open lower limb fractures. Materials and Methods: This prospective comparative study was conducted in the Department of Orthopaedics, Narayan Medical College and Hospital, Sasaram, over a period of 1 year and 8 months. A total of 30 patients aged 18 years and above with Gustilo–Anderson Grade IIIB and IIIC open lower limb fractures were included. Each patient was evaluated using both MESS and GHOISS at presentation. Clinical details, mechanism of injury, limb involvement, management strategies, and outcomes were recorded. Statistical analysis was performed using SPSS software, with appropriate descriptive and inferential tests. Results: The study population predominantly consisted of middle-aged males, with road traffic accidents being the most common mechanism of injury. Most fractures were classified as Gustilo–Anderson Grade IIIB. According to MESS, 90% of limbs were predicted to be salvageable, while GHOISS categorized 73.3% as salvageable, 13.3% as requiring amputation, and 13.3% falling into a grey zone. Overall limb salvage was achieved in 76.7% of patients. Both scoring systems correlated with clinical outcomes; however, GHOISS provided more detailed stratification by incorporating soft tissue, skeletal, functional, and systemic factors, particularly in borderline cases. Conclusion: Both MESS and GHOISS are useful tools in the assessment of severe open lower limb injuries. However, GHOISS offers a more comprehensive and practical framework for decision-making in Gustilo–Anderson Grade III fractures, especially in complex injuries requiring reconstructive procedures. Its ability to identify grey-zone cases allows for individualized clinical judgment, potentially reducing failed salvage attempts and improving overall outcomes.