Correlative microscopy is the application of two or more distinct microscopy techniques to the same region of a sample, generating complementary morphological and structural information that exceeds what is possible with any single technique to answer a biological question. We propose an approach based on a multimodal correlative microscopy, via two imaging and analytical techniques: fluorescence microscopy (FM) and ion beam analysis (IBA) to investigate in vitro nanoparticles (NPs) interactions. Indeed, the explosive growth in Nanotechnology has led to their utilization in a wide range of applications from therapeutics to multimodal imaging labeling. However, the risks for adverse health effects have not been clearly established. Detecting and tracking nanomaterials in biological systems are thus challenging and essential to understand the possible NPs-induced adverse effects. Indeed, assessing in situ NPs internalization at the single cell level is a difficult but critical task due to their potential use in nanomedicine. One of the main actual challenges is to control the number of NPs internalized per cell. The data obtained by both FM and IBA were strongly correlated in terms of detection, tracking, and colocalization of fluorescence and metal detection. IBA provides the in situ quantification not only of exogenous elements in a single cell but also of all the other endogenous elements and the subsequent variation in their cellular homeostasis. This unique property gives access to dose-dependent response analyses and therefore new perspectives for a better insight on the effect of metal oxide NPs on cellular homeostasis.