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Background: Common ragweed has been spreading as a neophyte in Europe. Elevated CO2 levels, a hallmark of global climate change, have been shown to increase ragweed pollen production, but their effects on pollen allergenicity remain to be elucidated. Methods: Ragweed was grown in climate‐controlled chambers under normal (380 ppm, control) or elevated (700 ppm, based on RCP4.5 scenario) CO2 levels. Aqueous pollen extracts (RWE) from control‐ or CO2‐pollen were administered in vivo in a mouse model for allergic disease (daily for 3‐11 days, n = 5) and employed in human in vitro systems of nasal epithelial cells (HNECs), monocyte‐derived dendritic cells (DCs), and HNEC‐DC co‐cultures. Additionally, adjuvant factors and metabolites in control‐ and CO2‐RWE were investigated using ELISA and untargeted metabolomics. Results: In vivo, CO2‐RWE induced stronger allergic lung inflammation compared to control‐RWE, as indicated by lung inflammatory cell infiltrate and mediators, mucus hypersecretion, and serum total IgE. In vitro, HNECs stimulated with RWE increased indistinctively the production of pro‐inflammatory cytokines (IL‐8, IL‐1β, and IL‐6). In contrast, supernatants from CO2‐RWE‐stimulated HNECs, compared to control‐RWE‐stimulated HNECS, significantly increased TNF and decreased IL‐10 production in DCs. Comparable results were obtained by stimulating DCs directly with RWEs. The metabolome analysis revealed differential expression of secondary plant metabolites in control‐ vs CO2‐RWE. Mixes of these metabolites elicited similar responses in DCs as compared to respective RWEs. Conclusion: Our results indicate that elevated ambient CO2 levels elicit a stronger RWE‐induced allergic response in vivo and in vitro and that RWE increased allergenicity depends on the interplay of multiple metabolites. [ABSTRACT FROM AUTHOR]