Introduction Amputation poses significant challenges encompassing psychological, physical, and socio-economic dimensions, impacting individuals and society at large. In India, a substantial portion of the population faces loco-motor disabilities, with amputees forming a notable segment. Prosthetic rehabilitation plays a crucial role in mitigating the consequences of limb loss, aiming to restore autonomy post-amputation. Methods A prospective cross-sectional observational study was conducted over 18 months, from November 2018 to May 2020, involving unilateral upper limb amputees (ULAs) aged over 18 years. A consecutive cohort of 33 patients, predominantly male (30 males and three females), with a mean age of 43 ± 12 years (median: 43 years; range: 20-67 years), was prospectively enrolled in the study. Participants had completed at least one month of post-prosthetic fitment and were actively attending outpatient or prosthetic checkout clinics. The study utilized the Manipal Prosthetic Rehabilitation Success (PRS) score and the Orthotics and Prosthetics User Survey Upper Extremity Functional Status (OPUS UEFS) score to assess prosthesis usage and functional status. Statistical analyses included descriptive statistics, Chi-square tests, Mann-Whitney U tests, Kruskal-Wallis tests, and multivariate logistic regression analysis. Results The study revealed insights into upper limb prosthesis usage in India, highlighting factors influencing the success and challenges faced by ULAs. Associations were found between the success of prosthesis usage and several factors: occupation type (p=0.012), the side of amputation involving non-dominant limbs (p=0.033), comfort level (p=0.002), and prosthesis weight (p=0.029). Comfort level emerged as a primary predictor of usage success. The OPUS UEFS scores indicated varying levels of satisfaction and usage patterns among participants, with some utilizing prostheses for specific tasks while others for broader activities. Comfort level demonstrated a statistically significant difference in OPUS UEFS scores, favoring comfortable prostheses (p=0.020). Additionally, the mean OPUS UEFS score for patients with satisfactory or good prosthesis use was 53 ± 11 (median: 55; range: 22-64), compared to 45 ± 13 (median: 43; range: 18 - 64) in those with poor prosthesis use, with the difference nearing statistical significance (p=0.058). Conclusion The study sheds light on the landscape of upper limb prosthesis usage in India, emphasizing the need for tailored interventions based on individual needs and cultural contexts. The findings underscore the importance of comfort, side of amputation involving non-dominant limbs, occupation type, and prosthesis weight in determining the success of prosthesis usage. Opportunities exist to enhance upper limb prosthetic care in India by addressing cultural nuances and refining assessment tools to better suit the Indian population.