A network of intersecting molecular pathways interacts to initiate and execute axon destruction. Maximum protection against axon degeneration likely requires more than manipulation of a single target. Here, we describe the process of designing a high-throughput arrayed screening assay for the identification of key factors responsible for axon destruction and/or protection. First, we go over some existing screens in the literature, then discuss the planning, tracking, analysis, and statistics around such a screening experiment. Prioritization of perturbations may allow laboratories to cost-effectively explore the process of screening. We also present the pairing of a combinatorial drug screen with a machine learning algorithm, predicting how to best modulate neurodegenerative and neuroprotective components.