Sceletium tortuosum (SCT) has been utilized medicinally by indigenous Koi-San people purportedly for mood elevation. SCT extracts are reported to be neuroprotective and have efficacy in improving cognition. However, it is still unclear which of the pharmacological mechanisms of SCT contribute to the therapeutic potential for neurodegenerative disorders. Hence, this study investigated two aspects-firstly, the abilities of neuroprotective sub-fractions from SCT on scavenging radicals, inhibiting some usual targets relevant to Alzheimer's disease (AD) or Parkinson's disease (PD), and secondly utilizing the network pharmacology related methods to search probable mechanisms using Surflex-Dock program to show the key targets and corresponding SCT constituents. The results indicated sub-fractions from SCT could scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, inhibit acetylcholinesterase (AChE), monoamine oxidase type B (MAO-B) and N-methyl-D-aspartic acid receptor (NMDAR). Furthermore, the results of gene ontology and docking analyses indicated the key targets involved in the probable treatment of AD or PD might be AChE, MAO-B, NMDAR subunit2B (GIuN2B-NMDAR), adenosine A(2A) receptor and cannabinoid receptor 2, and the corresponding constituents in Sceletium tortuosum might be N-trans-feruloyl-3-methyldopamine, dihydrojoubertiamine and other mesembrine type alkaloids. In summary, this study has provided new evidence for the therapeutic potential of SCT in the treatment of AD or PD, as well as the key targets and notable constituents in SCT. Therefore, we propose SCT could be a natural chemical resource for lead compounds in the treatment of neurodegenerative disorders.