The instability of most prototype metal–organic frameworks (MOFs) in the presence of water has limited their industrial scale development. The sensitivity of certain MOFs to humid conditions has been vigorously studied and most of the carrier gas used to make the humid conditions is inert gas. However, a large amount of industrial activities are carried out in air containing 21% oxygen, so it is important to study the effect of oxygen on the hydrostability of MOFs for future industrial applications. In this work, we have studied the stability of M₃(BTC)₂ (M = Cu, Cr; BTC = 1,3,5-benzenetricarboxylate) under controlled environments (pure oxygen environment; water vapor environment and mixed O₂ and H₂O environment). The stability was evaluated using water vapor and oxygen adsorption isotherms combined with powder X-ray diffraction (PXRD) experiments and surface area analysis. Our research shows that Cr₃(BTC)₂ has a relatively high stability under a single atmosphere of either oxygen or water vapor (with Ar). Interestingly, when it was placed under the mixed O₂ and H₂O environment, it rapidly lost approximately 96% of its original surface area. Cu₃(BTC)₂ is more stable; however, it was also degraded, especially under a mixed O₂ and H₂O environment. The experiments show that water molecules and oxygen molecules have a synergistic effect on the stability of MOFs. Computational simulations were used to provide insight into the mechanism governing these trends in the stability of the materials studied.