Metal–organic frameworks (MOFs) are being investigated as the potential materials for future drug delivery and gene therapy systems thanks to their tunable functionality and biocompatibility. However, the structure of MOFs could be altered in a biological environment or in a buffer solution. It is of great importance to evaluate the stability of MOFs and understand the degradation processes for the sake of the biomedical applications. In this work, we investigate the stability of UiO-66, a generally-perceived stable MOF, in different amino acid solutions. We find that UiO-66 loses crystallinity in relatively mild basic conditions (when pH ≥ 9) in the presence of amino acids. The instability is more pronounced in the lysine and arginine solutions which have stronger basicity. It can be attributed to the accelerated ligand exchange of UiO-66 under basic conditions. With a combination of techniques, we show that the amino acids can replace the organic linkers and form zirconium-amino acid complexes. Our research reveals one possible mechanism of MOF degradation in biological environment, yet such degradability could be also an important designable property for MOFs in biomedical applications.