The mutation-induced changes across protein-protein interfaces have often been observed to lead to severe diseases. Therefore, several computational tools have been developed to predict the impact of such mutations. Among these tools, FoldX and EvoEF1 stand out as fast and accurate alternatives. Expanding on the capabilities of these tools, we have developed the PROT-ON (PROTein-protein interface mutatiONs) framework, which aims at delivering the most critical protein interface mutations that can be used to design new protein binders. To realize this aim, PROT-ON takes the 3D coordinates of a protein dimer as an input. Then, it probes all possible interface mutations on the selected protein partner with EvoEF1 or FoldX. The calculated mutational energy landscape is statistically analyzed to find the most enriching and depleting mutations. Afterward, these extreme mutations are filtered out according to stability and optionally according to evolutionary criteria. The final remaining mutation list is presented to the user as the designer mutation set. Together with this set, PROT-ON provides several residue- and energy-based plots, portraying the synthetic energy landscape of the probed mutations. The stand-alone version of PROT-ON is deposited at https://github.com/CSB-KaracaLab/prot-on. The users can also use PROT-ON through our user-friendly web service http://proton.tools.ibg.edu.tr:8001/ (runs with EvoEF1 only). Considering its speed and the range of analysis provided, we believe that PROT-ON presents a promising means to estimate designer mutations.