The increase of human and environmental exposure to engineered nanomaterials (ENMs) due to the emergence of nanotechnology has raised concerns over their safety. The challenging nature of and toxicity assessment methods for ENMs, has led to emerging techniques for ENM toxicity assessment, such as structure-activity relationship (SAR) models. Although such approaches have been extensively developed for the case of single-component nanomaterials, the case of multicomponent nanomaterials (MCNMs) has not been thoroughly addressed. In this paper, we present a SAR approach for the case metal and metal oxide MCNMs. The developed SAR framework is built using a dataset of 796 individual toxicity measurements for 340 different MCNMs, towards human cells, mammalian cells, and bacteria. The novelty of the approach lies in the multicomponent nature of the nanomaterials, as well as the size, diversity and heterogeneous nature of the dataset used. Furthermore, the approach used to calculate descriptors for surface loaded MCNMs, and the mechanistic insight provided by the model results can assist the understanding of MCNM toxicity. The developed models are able to correctly predict the toxic class of the MCNMs in the heterogeneous dataset, towards a wide range of human cells, mammalian cells and bacteria. Using the abovementioned approach, the principal toxicity pathways and mechanisms are identified, allowing a more holistic understanding of metal oxide MCNM toxicity.