In the aerospace industry, a large number of holes need to be drilled to mechanically connect the components of aircraft engines. The working conditions for such components demand a good response of their mechanical properties at high temperatures. The new gamma TiAl are in the transition between the 2nd and 3rd generation, and several applications are proposed for that sector. Thus, NASA is proposing the use of the alloys in the Revolutionary Turbine Accelerator/Turbine-Based Combined Cycle (RTA/TBCC) Program for the next-generation launch vehicle, with gamma TiAl as a potential compressor and structural material. However, the information and datasets available regarding cutting performance in titanium aluminides are relatively scarce. So, a considerable part of the current research efforts in this field is dedicated to process optimization of cutting parameters and tool geometries. The present work is framed in the study of wear when machining holes in these difficult-to-cut alloys. In particular, the work presents the results from drilling tests on three types of gamma TiAl alloys, extruded MoCuSi, ingot MoCuSi, and TNB type, to define an optimal set of cutting parameters. Maintaining uniform, gradual wear is key to avoiding tool breakage and enabling good hole dimensional accuracy. So, this paper proposes a model based on ANOVA analysis to identify the relationships between cutting conditions and resulting wear and estimate tool life. The best cutting parameters were found at vc = 10–15 m/min and fn = 0.025 mm/rev.