The negative effects of particulate matter up to 2.5 μm in diameter (PM2.5) and their mediating mechanisms have been studied in various tissues. However, little is known about the mechanism and long-term tracking underlying the sex-dependent effects of PM2.5 on skeletal muscle system modulation. During youth, skeletal muscle grows rapidly and develops at its highest rate. Here we explore how exposure to atmospherically relevant levels of artificial PM2.5 affects the skeletal muscle system in 4-week-old C57BL6 mice according to sex and track the effects for 15 months post-exposure. We found that PM2.5 retarded muscle fiber growth and caused mitochondrial damage by modulating factors related to mitochondrial kinetics. However, the effects of PM2.5 on the modulation of the skeletal muscle system differed by sex and post-exposure time. The negative impacts of PM2.5 on skeletal muscle continued until they were overwhelmed by aging-related oxidative stress and inflammation, which were more severe in older PM2.5-exposed female mice compared with male mice. Older PM2.5-exposed female mice, but not older PM2.5-exposed male mice, exhibited obesity-related phenotypes in the form of increased weight and fat mass. Overall, initial exposure to PM2.5 affected the skeletal muscle system with long-lasting impacts that differed according to sex.