Air pollution is a widespread global environmental hazard that poses significant threats to both human health and the earth’s ecosystems. Particulate matter (PM2.5) is one of the most perilous forms of air pollution if present in higher concentrations. This tiny material is incorporated into the air by both anthropogenic and natural activities and may further lead to poor ambient air quality. The size of these particles has been directly linked to their reactivity and potential impact on human health. Inhalable coarse particles 2.5 to 10 μm in diameter and fine particles < 2.5 μm in diameter are the primary concern due to their high surface-to-volume ratio. Owing to their diverse physicochemical characteristics, such as the heterogeneous mixture of particle sizes, small diameters, and chemical components, PM2.5 have been found to be associated with many respiratory and reproductive-related disorders, cardiovascular diseases, central nervous system dysfunctions, and cancer. In this review article, we have highlighted the sources, occurrence, and human toxicological effects of PM2.5, as well as their role in the progression of various human diseases. Various preclinical and epidemiological studies are also covered to reveal the harmful effects of PM2.5 on human health worldwide. This comprehensive analysis of PM2.5 may help policymakers and other stakeholders adopt more stringent measures to phase out PM2.5 levels and mitigate its negative impacts on human health and the ecosystem.