Assessment of the influence of volatile organic compounds (VOCs) on allergic symptoms is usually limited to the effect of individual VOC exposure, with fewer substances being considered. Furthermore, the impact of mixed VOC exposure on allergic symptoms has rarely been addressed. This study aimed to investigate the association between mixed VOC exposure and allergic symptoms while identifying key risk factors. A total of 1901 participants from the 2005-2006 National Health and Nutrition Examination Survey (NHANES) were included. Four statistical models were employed to assess the effect of VOC exposure on allergic symptoms. The potential pathways and key targets were identified using the network pharmacology analysis methods. Positive correlations were observed between mixed VOC exposure and wheezing and eczema. N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA) and N-acetyl-s-(3-hydroxypropyl-1-methyl)-L-cysteine (HPMM) were recognized as significant risk factors for wheezing and eczema. The network pharmacology analysis revealed significant enrichments of the PI3K-Akt and MAPK signaling pathways between AAMA and wheezing, as well as significant enrichments of the interleukin (IL)-17 and tumor necrosis factor (TNF) signaling pathways between HPMM and eczema. Consequently, our study suggested that VOC exposure in human results in oxidative stress and inflammatory responses, increasing the risk of allergic symptoms.