Abstract Background This study conducted to determine the prevalence and severity of musculoskeletal discomfort among two-wheeler riders; however, musculoskeletal discomfort refers to pain, discomfort, or impairment in the muscles, bones, joints, tendons, ligaments, or other structures that support the body’s movement. It is a common problem experienced by individuals involved in various physical activities, including motorcycle riding. Methods This investigation was longitudinal research in which the Nordic muscular questionnaire (NMQ) was used to rule out the possibility of musculoskeletal disorders in motorcyclists. In Karachi, Pakistan, data were collected beginning in September of 2021 and continuing through February of 2022 using the convenience sampling method. Sixty-four individuals made up the sample. Participants were males ranging between the ages of 19 and 50 who rode standard motorcycles for their commute for about 6 to 8 h daily. Participants who had a tumor, an infection, or other comorbid are excluded. Results Sixty-four participants were included in this study, out of which 40 (62.5%) reported difficulty and discomfort in their neck, followed by their lower back (48.5%), shoulders (34.4%), and hips (26.6%). Sixteen motorcyclists (25%) complained wrist pain. When asked out their level of discomfort. However, 51.6% of individuals experienced lower back pain at the 12th month, while 46.9% had neck pain. 28.1%, 17.2%, and 14.1% reported shoulder, hip, and upper back discomfort. 51.6% of individuals had not seen a specialist for lower back symptoms. Lower back, neck, shoulders, and hip have been affected the longest, according to participants. Conclusion In conclusion, motorcyclists had a substantially greater rate of musculoskeletal problems than other drivers. Regulating musculoskeletal disorders in motorcyclists helps reduce symptoms and clinical indications of disease.