Unveiling the mechanisms of gene-environment and host–parasite interactions in vivo and how they impact human immune response are challenging. We combine prospective population sampling and multi-omics profiling with a focus on studying genomes, transcriptomes and metabolomes across ethnic groups and lifestyles. This approach provided a high-resolution depiction of molecular perturbations induced in vivo by P. falciparum and revealed clinically relevant molecular nuances and host-parasite interactions within the human host.