We report a CrISe monolayer as a room temperature ferromagnetic (FM) semiconductor with the Curie temperature (TC), magnetic anisotropy energy (MAE), and bandgap being 322 K, 113 μeV, and 1.76 eV, respectively. The TC and MAE can be further enhanced up to 385 K and 313 μeV by a tensile strain. Interestingly, the magnetic easy axis can be switched between off-plane and in-plane by compressive strain. Particularly, due to the broken inversion symmetry and strong spin–orbital coupling of Se atoms, a large Dzyaloshinskii–Moriya interaction (DMI) of 2.40 meV is obtained. More importantly, by micromagnetic simulations, stable skyrmions with sub-10 nm radius are stabilized by the large DMI above room temperature in a wide range of strain from −2% to 6%. Our work demonstrates CrISe as a promising candidate for next-generation skyrmion-based information storage devices and provides guidance for the research of DMI and skyrmions in room temperature FM semiconductors.