The most prominent form of nonlinear optical (NLO) frequency conversion is second harmonic generation (SHG), where incident light interacts with a nonlinear medium producing photons at double the input frequency, which has vast applications in material and biomedical science. Emerging two-dimensional nonlinear optical materials led by transition metal dichalcogenides (TMDs) have fascinating optical and mechanical properties and are highly anticipated to overcome the technical limitations imposed by traditional bulky NLO materials. However, the atomic scale interaction length and low conversion efficiency in TMD materials prevent their further implementation in NLO applications. While some uniaxial strain-engineering studies intensively investigated the anisotropic SHG response in TMDs, they did not realize giant SHG enhancement by exploiting the opto-mechanical characteristics. Herein, we employ proton (H+) irradiation to successfully fabricate large pressurized monolayer TMD domes (d ≥ 10 μm) and conduct a comprehensive investigation and characterization of their SHG performance enhancement. We show that the intensity of SHG is effectively enhanced by around two orders of magnitude at room temperature. Such giant enhancement arises from the distinct separation distance induced by capped pressurized gas and the hemi-spherical morphology, enabling constructive optical interference. Moreover, the unique divergent strain field in TMD domes promotes the first experimental study on the anisotropic nonlinear optical behavior based on biaxial strain conditions in terms of varying strain orientation and relative weights. Our work demonstrates a promising system with enhanced NLO performance and well-preserved biocompatibility, paving a way toward the future nano-scaled quantum optics design and biomedical applications.