Fine particulate matter (PM_2.5) poses a significant global environmental health threat and is closely associated with diseases across multiple organ systems. This review systematically summarizes the toxic effects and underlying mechanisms of PM_2.5 in the respiratory, cardiovascular, nervous, immune, endocrine, digestive, and genitourinary systems. Key pathogenic processes involve shared pathways such as oxidative stress, inflammatory responses, endoplasmic reticulum stress, autophagy, and apoptosis, along with the activation of system-specific signaling networks. The complex composition and notable spatiotemporal variability of PM_2.5 present challenges for assessing its health risks and clarifying its mechanisms. Moving forward, integrating multi-omics and molecular epidemiology approaches will be essential to unravel its multi-system pathogenic networks and support the development of effective intervention strategies.