Background and Objectives: Avian influenza poses a continuous public health threat, particularly to individuals with occupational exposure to poultry such as farm workers, live animal market employees, and processing plant staff. This study aimed to investigate the systemic metabolic effects of such exposure and to identify potential biomarkers for early detection and health risk assessment. Materials and Methods: An untargeted liquid chromatography–mass spectrometry (LC-MS)-based metabolomics approach was applied to analyze serum samples from occupationally exposed individuals and healthy controls. Multivariate statistical analysis, pathway enrichment, and topology analysis were performed to identify significantly altered metabolites and metabolic pathways. The least absolute shrinkage and selection operator (LASSO) algorithm was employed to select key metabolites. Results: Multivariate statistical analysis revealed a clear separation between the exposure group and control, suggesting distinct metabolic profiles between the two populations. Pathway analysis indicated significant alterations in alanine, aspartate, and glutamate metabolism, as well as tryptophan metabolism, which are closely linked to immune regulation, energy metabolism, and host–pathogen interactions. LASSO feature selection and subsequent manual verification identified 17 key metabolites with strong discriminative power. Furthermore, lipidomic profiling revealed a pronounced increase in lysophosphatidylcholine (LPC) levels and a concurrent decrease in phosphatidylcholine (PC) species in exposed individuals. Conclusions: This study reveals metabolic disruptions associated with occupational avian influenza exposure and identifies potential serum biomarkers related to immune and lipid metabolism. These findings provide novel insights into host responses to avian influenza exposure and may support early detection and health risk assessment in high-risk occupational populations.