Poor muscle function is increasingly obvious with aging and needs effective and safe medicine for treatment. Trimetazidine (TMZ) has potential benefits for the condition but has not yet been fully recognized. In the randomized-control pilot study part, fifty-three old patients were assigned to the TMZ group or control group. For the TMZ group, a dose of 35 mg of oral TMZ was administered with a meal twice a day for 3 months. Only conventional treatments were administrated in the control group. Muscle strength, gait speed, muscle endurance, and balance maintenance were measured during the visits. In the experiments part, thirty mice were screened and randomly assigned to three groups: model group received a D-gal (500 mg/kg) intraperitoneal injection every two days for six weeks, the control group received saline at the same condition, and the intervention group received 5 mg/kg TMZ solution every two days by gavage for two weeks. Swimming tests and forelimb grip strength measurements were also performed. Furthermore, significantly clustered profiles from differentially expressed genes were found by RNA-seq and verified by qRT-PCR and WB. Myofiber analyses were done by H&E staining. Here, we found the improvement of skeletal performance in aged individuals and aged mouse. The dominant handgrip strength (HS) was increased by 24.4% and dominant pinch strength (PS) by 12.4% in participants with TMZ modified-release tablets consumption. Exhaustive time was increased by 23.6% and upper limb grip strength by 44.1% in aged mouse with TMZ-treated. Besides, we also identified some newly discovered molecules associated with TMZ on muscle function improvement during aging. To aged C2C12 cells and aged mouse muscle, TMZ-treated was related to a statistically significant decrease in the expressions of NOS3 and MMP-9, but a statistically significant increase in the expressions of OMD and MyoG. In summary, TMZ modified-release tablets can improve the muscle strength of elderly patients. Besides, the improvement of skeletal muscle function affected by TMZ was associated with reducing NOS3 expression in senescent myoblasts.