Main conclusionsC. campestris parasitisation increases internal host defences at the expense of environmentally directed ones in the host species A. campestris, thus limiting plant defence against progressive parasitisation.Cuscuta campestris Yunck is a holoparasitic species that parasitises wild species and crops. Among their hosts, Artemisia campestris subsp. variabilis (Ten.) Greuter is significantly affected in natural ecosystems. Limited information is available on the host recognition mechanism and there are no data on the interactions between these species and the effects on the primary and specialised metabolism in response to parasitisation. The research aims at evaluating the effect of host–parasite interactions, through a GC–MS untargeted metabolomic analysis, chlorophyll a fluorescence, ionomic and δ13C measurements, as well as volatile organic compound (VOC) fingerprint in A. campestris leaves collected in natural environment. C. campestris parasitisation altered plant water status, forcing stomatal opening, stimulating plant transpiration, and inducing physical damages to the host antenna complex, thus reducing the efficiency of its photosynthetic machinery. Untargeted-metabolomics analysis highlighted that the parasitisation significantly perturbed the amino acids and sugar metabolism, inducing an increase in the production of osmoprotectants, which generally accumulate in plants as a protective strategy against oxidative stress. Notably, VOCs analysis highlighted a reduction in sesquiterpenoids and an increase in monoterpenoids levels; involved in plant defence and host recognition, respectively. Moreover, C. campestris induced in the host a reduction in 3-hexenyl-acetate, a metabolite with known repellent activity against Cuscuta spp. We offer evidences that C. campestris parasitisation increases internal host defences via primary metabolites at the expense of more effective defensive compounds (secondary metabolites), thus limiting A. campestris defence against progressive parasitisation.