Ti-6Al-4V is a benchmark Ti alloy. Laser wire additive manufacturing (LWAM) offers advanced manufacturing capability to the alloy for applications possibly including exploration of outer space. As a typical multiple-variable process, LWAM is complex, which, however, can be analyzed, predicated or even optimized by artificial intelligence (AI) methods such as machine learning (ML). In this study, printing parameters of the Ti-6Al-4V is firstly optimized using single-track-single-layer experiments, and then single-track-multiple-layer samples are printed, whose properties in terms of hardness and compressive strength are analyzed subsequently by both experiments and ML. The two ML approaches, artificial neural network (ANN) and support vector machine (SVM), are employed to predict the experimental results, whose coefficients of determination R² show good values. Further optimized properties are realized by adopting genetic algorithm (GA) and simulated annealing (SA) approaches, which contribute to high mechanical properties achieved, for instance, an engineering compressive strength of about 1694 MPa. The results here indicate that important mechanical properties of the LWAM-prepared Ti alloys can be well predicted and enhanced using suitable ML approaches.