Mechanical engineering plays an important role in the design and manufacture of medical devices, implants, prostheses, and other medical equipment, where the machining of bio-compatible materials have a special place. There are a lot of different conventional and non-conventional types of machining of biocompatible materials. One of the most frequently used methods is milling. The first part of this research explores the machining parameters optimization minimizing surface roughness in milling titanium alloy Ti-6Al-4V. A full factorial design involving four factors (cutting speed, feed rate, depth of cut, and the cooling/lubricating method), each having three levels, implies the 81 experimental runs. Using the Taguchi method, the number of experimental runs was reduced from 81 to 27 through an orthogonal design. According to the analysis of variance (ANOVA), the most significant parameter for surface roughness is feed rate. The second part explores the possibilities of using different ML techniques to create a predictive model for average surface roughness using the previously created small datasets. The paper presents a comparative analysis of several commonly used techniques for handling small datasets and regression problems. The best results indicate that the widely used machine learning algorithm Random Forest excels in handling regression problems and small datasets.