By using first-principles calculations, the electronic properties and chemical activity of phosphorene under the strain and defect engineering are studied. Furthermore, the effects of engineering on the interactions of NO gas molecule and humidity (H2O) and air (O2) molecules with the phosphorene surface are investigated. It is found that phosphorene enables to withstand a large compressive strain, up to −35%, and exhibit anisotropic electronic properties. Moreover, compressive strain and the presence of mono- and di-vacancy defects significantly alter the chemical activity of phosphorene as indicated by the enhanced adsorption and charge transfer between considered molecules and phosphorene surface. Thus, our findings suggest phosphorene as a perspective material for optical and photovoltaic applications.