Nickel-based superalloys are heavily used in the aerospace and power industries due to their excellent material and mechanical properties. They offer high strength at elevated temperatures, high hardness, corrosion resistance, thermal stability and improved fatigue properties. These superalloys were developed to address the demand for materials with the enhanced heat and stress capabilities needed to increase operational temperatures and speeds in jet and turbine engines. However, most of these properties come with machining difficulty, high wear rate, increased force and poor surface finish. Rene 65 is one of the next generation wrought nickel superalloys that addresses these demands at a reduced cost versus powder metallurgy superalloys. It is strengthened by the presence of gamma prime precipitates in its microstructure, which enhance its strength at high temperatures. Notwithstanding its advantages, Rene 65 must also deal with the reality of the poor workability and machinability generally associated with Ni-based superalloys. This study examines the machinability—using drilling tests—of Rene 65 and seeks to establish the influence of hardness (with varying microstructure) and cutting conditions on machinability indicators (surface finish, forces and chip formation). The experimental setup is based on a set of experimental drilling tests using three different heat-treated samples of varying hardness. The results indicate a negligible effect from material hardness, ranging from 41 HRC to 52 HRC, on generated cutting forces and a similarly low effect from cutting speeds. The feed rate was identified as the main factor of relevance in cutting force and chip morphology during the machining of this new superalloy.