People with hemophilia (PwH) often present with a range of musculoskeletal conditions, including muscle atrophy, weakness, limited range of motion, and persistent pain, which can lead to impairment in functional and health-related quality of life (HRQoL). The perceived quality of life of adult hemophilia patients is worse than that of the healthy population. Access to pharmacological treatment, particularly prophylaxis, has significantly improved the survival and quality of life of PwH. Hemophilia severity and persistent pain, which can affect up to 46% of the patients, are also relevant predictors of HRQoL. Being able to exercise has been proven to protect against joint deterioration in PwH. Physical activity has numerous benefits for PwH, including improving muscle strength, flexibility, balance, and even reducing bleeding tendencies. Additionally, strength training with elastic resistance improves the quality-of-life dimension of perceived joint damage and perceived functional abilities. However, it is important for health professionals to recognize that participation in physical activity by PwH is affected by external variables (e.g., family, friends, health professionals, structures, and community). On the other hand, catastrophizing and kinesiophobia can negatively impact the quality of life of PwH. Thus, non-pharmacological treatment, such as cognitive behavioral therapy combined with physiotherapy, has proven effective in reducing pain and kinesiophobia, while improving the quality of life and emotional state of PwH. Symptoms of depression and anxiety occur more frequently with increasing severity of hemophilia, negatively affecting HRQoL. In this context, a comprehensive psychological assessment, including appropriate screening for symptoms of anxiety and depression, as well as an early holistic therapeutic approach, is warranted in hemophilia care. Finally, social participation can have a significant impact on the quality of life of PwH. It is therefore necessary to promote social participation in this population. In conclusion, access to appropriate tailor-made treatments and emotional and social support would be crucial elements to improve the quality of life of PwH.