The malaria parasite Plasmodium falciparum encounters diverse environments throughout its asexual lifecycle, including high parasite densities during sequestration of trophozoites and schizonts in the microvasculature. High parasite densities in the human host have been associated with severe malaria in vivo, while regulation of parasite populations below the fever-inducing threshold has been observed in asymptomatic children in Papua New Guinea [1]. Such disparate behaviour suggests a key role for parasite responses to density with respect to disease progression and severity. In vitro cultures of high density, asexual P. falciparum exhibited aberrant morphology during the late trophozoite and schizont stages. These were arrested development, failure of schizont maturation and merozoite formation, and hallmarks of cell death such as loss of cell volume, mitochondrial membrane depolarization, and blebbing of the parasite plasma membrane with eventual release of aberrant parasites from infected erythrocytes. The density-dependent cell death was not a consequence of glucose or essential amino acid depletion or excess lactate. A multi-omics analysis was performed to characterize the transcriptomic, metabolic, and lipid profiles within the local environment of P. falciparum in vitro cultures at densities corresponding to severe malaria. Metabolic analysis of conditioned medium derived from high-density parasite cultures revealed perturbation of compounds involved in amino acid and carbohydrate metabolism, as well as depletion of glycerophospholipids. Individual ‘omics platforms were integrated using a latent component discriminant analysis (DIABLO), identifying a subset of features that described the effects of density on parasite metabolism and were highly correlated across ‘omics platforms. Gene ontology analysis of features selected by integrated analysis illustrated the relatedness of biological pathways perturbed under high-density conditions. Ultimately, this systems biology approach to characterizing parasite metabolism in high-density environments may highlight potential targets for intervention.