Litharge, in two dimensional (2D) nanostructure form, has recently ignited considerable theoretical interest due to its excellent photoelectric and magnetic properties. However, the lack of an efficient synthesis method hinders its development. Here, we provide an interfacial solvothermal strategy for controllably synthesizing ultrathin hexagonal polycrystalline α-PbO nanosheets in micrometer scale. This strategy can also be utilized for the synthesis of other 2D materials. Experimental atomic force microscope nanoindentation measurements reveal the relationship between the thickness of polycrystalline α-PbO nanosheets and the corresponding Young’s modulus, expressed as E = E0 + Kt−1. First-principles calculation supports the result and ascribes the cause to interlayer sliding from particular weak interlayer interactions. Additionally, the enhanced mechanical strength of the polycrystalline structure compared to its single-crystal counterpart is attributed to the alternate arrangement of grain-boundaries effects. The summative formula may be extended to other 2D materials with weak interlayer interactions, which has the potential to provide guidance for constructing flexible devices.