Objectives: The onset and advancement of silicosis are intricately linked to immune system activation and oxidative stress. We aimed to examine whether occupational silica exposure induces alterations in neopterin levels, the immune system, or the oxidant/antioxidant system. Methods: Fifty-two healthy individuals, 47 workers with silica exposure who did not develop the disease, and 71 silicosis patients were included in the study, totaling 170 participants. Neopterin was measured in serum and urine. Chromatographic analysis of neopterin level was performed with Thermo Ultimate 3000 ultra-high-performance liquid chromatography system. Tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ), fibroblast growth factor (FGF), interleukin (IL)-1α, IL-1β, 8-hydroxy-2-deoxyguanosine (8-OH-dG), glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) were measured in serum. Immune and oxidative stress parameters were measured by spectrophotometric and spectrofluorometric methods. Results: Serum neopterin levels were significantly different between the study groups, while urinary neopterin levels were not. Serum neopterin levels were significantly decreased in the silicosis group compared to the exposure and non-exposed group groups. TNF-α, IFN-γ, FGF, IL-1α, 8-OH-dG, and GR increased with silica exposure, while SOD and GPx decreased. Serum neopterin, IL-1α, GR, age, and forced expired volume (FEV1%) were found to be risk factors for silicosis development. A negative correlation existed between neopterin levels, TNF-α, and overall exposure duration. Conclusions: Neopterin is applicable in the diagnosis and monitoring of oxidative stress and alterations in the immune system associated with silicosis. Thus, it can ensure that preventive measures are taken at an early stage.