The development of the photostable higher-order multiphoton-excited (MPE) upconversion single microcrystalline material is fundamentally and technologically important, but very challenging. Here, up to five-photon excited luminescence in a host-guest metal-organic framework (MOF) and perovskite quantum dot (QD) hybrid single crystal ZJU-28⊃MAPbBr is shown via an in situ growth approach. Such a MOF strategy not only results in a high QD loading concentration, but also significantly diminishes the aggregation-caused quenching (ACQ) effect, provides effective surface passivation, and greatly reduces the contact of the QDs with the external bad atmosphere due to the confinement effect and protection of the framework. These advantages make the resulting ZJU-28⊃MAPbBr single crystals possess high PLQY of ≈51.1%, a high multiphoton action cross-sections that can rival the current highest record (measured in toluene solution), and excellent photostability. These findings liberate the excellent luminescence and nonlinear optical properties of perovskite QDs from the solution system to the solid single-crystal system, which provide a new avenue for the exploitation of high-performance multiphoton excited hybrid single microcrystal for future optoelectronic and micro-nano photonic integration applications.