Monolayer semiconductors with unique mechanical responses are promising candidates for novel electromechanical applications. Here, through first-principles calculations, we discover that the monolayer β -TeO2, a high-mobility p -type and environmentally stable 2D semiconductor, exhibits an unusual out-of-plane negative Poisson's ratio (NPR) when a uniaxial strain is applied along the zigzag direction. The NPR originates from the unique six-sublayer puckered structure and hinge-like Te-O bonds in the 2D β -TeO2. We further propose that the sign of the Raman frequency change under uniaxial tensile strain could assist in determining the lattice orientation of monolayer β -TeO2, which facilitates the experimental study of the NPR. Our results is expected to motivate further experimental and theoretical studies of the rich physical and mechanical properties of monolayer β -TeO 2 .