Introduction: The use of machine learning (ML) techniques in healthcare encompasses an emerging concept that envisages vast contributions to the tackling of rare diseases. In this scenario, amyotrophic lateral sclerosis (ALS) involves complexities that are yet not demystifed. In ALS, the biomedical signals present themselves as potential biomarkers that, when used in tandem with smart algorithms, can be useful to applications within the context of the disease. Methods: This Systematic Literature Review (SLR) consists of searching for and investigating primary studies that use ML techniques and biomedical signals related to ALS. Following the defnition and execution of the SLR protocol, 18 articles met the inclusion, exclusion, and quality assessment criteria, and answered the SLR research questions. Discussions: Based on the results, we identifed three classes of ML applications combined with biomedical signals in the context of ALS: diagnosis (72.22%), communication (22.22%), and survival prediction (5.56%). Conclusions: Distinct algorithmic models and biomedical signals have been reported and present promising approaches, regardless of their classes. In summary, this SLR provides an overview of the primary studies analyzed as well as directions for the construction and evolution of technology-based research within the scope of ALS.