Many attempts have been made to synthesize cadmium-free quantum dots (QDs) using nontoxic materials, while preserving their unique optical properties. Despite impressive advances, gaps in knowledge of their intracellular fate, persistence and excretion from the targeted cell or organism still exist, precluding clinical applications. In this study, we used a simple model organism (Hydra vulgaris) presenting a tissue grade of organization to determine the biodistribution of indium phosphide (InP) based QDs by X-ray fluorescence imaging. By complementing elemental imaging with In L-edge X-ray Absorption Near Edge Structure, unique information on in situ chemical speciation was obtained. Unexpectedly, spectral profiles indicated the appearance of In-O species within the first hour post-treatment, suggesting a fast degradation of the InP QD core in vivo, induced mainly by carboxylate groups. Moreover, no significant difference in the behaviour of bare core QDs and QDs capped with an inorganic Zn(Se,S) gradient shell was observed. The results paralleled those achieved by treating animals with an equivalent dose of indium salts, confirming the preferred bonding type of In3+ ions in Hydra tissues. In conclusion, by focusing on the chemical identity of indium along a 48 h long journey of QDs in Hydra, we describe a fast degradation process, in absence of evident toxicity. These data pave the way to new paradigms to be considered in the biocompatibility assessment of QD-based biomedical applications, with greater emphasis on the dynamic of in vivo biotransformations, and suggest strategies to drive the design of future applied materials for nanotechnology-based diagnosis and therapeutic.