Lower-limb amputation (LLA) has a profound impact on functional mobility, which is essential for maintaining independence and quality of life. With a rising number of LLAs performed annually, particularly due to diabetes-related complications, understanding the factors that influence mobility outcomes is critical for optimizing rehabilitation strategies. This systematic review aimed to identify and evaluate prognostic factors associated with functional mobility in adults with LLA. A comprehensive literature search was conducted in PubMed, EMBASE, CINAHL, and Cochrane databases, supplemented by gray literature sources, following PRISMA-P guidelines. Eligible studies examined various prognostic factors affecting mobility outcomes, which were assessed for quality using the Quality In Prognosis Studies tool. Fourteen studies were included, encompassing prospective, retrospective, and cross-sectional designs. Identified prognostic factors were categorized into 4 key domains: sociodemographic, medical, physical function, and psychological. Age, sex, comorbidities, and level of amputation emerged as primary determinants of mobility, with psychological factors such as cognitive function and mental health also playing a significant role. Although higher amputation levels, older age, and multiple comorbidities were associated with reduced mobility, mental well-being and male sex were linked to better outcomes. Limited evidence was found regarding other potential predictors, including race/ethnicity, prosthetic use, balance, employment status, and activity level, highlighting the need for further high-quality research. These findings emphasize the importance of a multidimensional rehabilitation approach that considers both physical and psychological factors to enhance mobility and overall well-being in individuals with LLA.