Two-dimensional (2D) magnetic materials with tunable magnetic anisotropy energy (MAE) are of great scientific interest and hold immense promise for ultracompact spintronic devices with lower energy consumption and higher storage density. Here, we demonstrate a practical approach for manipulating MAE in layered MnTe2 through the alkali metal adsorption and ferroelectric (FE) polarization effect. Our results reveal colossal MAE values of up to -12.428 erg/cm2 under Li/Na adsorption, accompanied by a spin reorientation and enhanced ferromagnetic (FM) coupling stability. Their negative MAE show a linear enhancement in response to the external strain. Moreover, we find that the FE In2Se3 substrate enhances the perpendicular magnetic anisotropy (PMA) of MnTe2 up to 2.318 erg/cm2 depending on the polarization direction. Ferroelectric switching at In2Se3-based interfaces could also induce significant MAE changes with the value of 3.838 erg/cm2. We elucidate that the underlying mechanisms for these modulations are primarily attributed to alterations in the electron occupancy of interfacial Te1-derived py and pz states, which affect their competitive spin-orbit coupling (SOC) strengths. These findings highlight the potential of interfacial engineering in tailoring magnetism in 2D materials, opening exciting possibilities for the development of advanced spintronic devices with enhanced functionality.