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Substances with modulatory capabilities on certain aspects of human cognition have been revered as nootropics from the dawn of time. The plant kingdom provides most of the currently available nootropics of natural origin. Here, in this systematic review, we aim to provide state-of-the-art information regarding proven and unproven effects of plant-derived nootropics (PDNs) on human cognition in conditions of health and disease. Six independent searches, one for each neurocognitive domain (NCD), were performed in parallel using three independent scientific library databases: PubMed, Cochrane and Scopus. Only scientific studies and systematic reviews with humans published between January 2000 and November 2021 were reviewed, and 256 papers were included. Ginkgo biloba was the most relevant nootropic regarding perceptual and motor functions. Bacopa monnieri improves language, learning and memory. Withania somnifera (Ashwagandha) modulates anxiety and social-related cognitions. Caffeine enhances attention and executive functions. Together, the results from the compiled studies highlight the nootropic effects and the inconsistencies regarding PDNs that require further research. ; Support for this work was provided by the Research and Education Council of the Comunidad de Madrid, Spain (2018-T1/BIO-10633) and Ministry of Science and Innovation, Spain (PID2020-114885RB-C21). Dr Aida Serra acknowledges a grant from the Talento Program 2018 of the Comunidad de Madrid. Dr. Xavier Gallart-Palau acknowledges grants from Sara Borrell postdoctoral program (CD19/00243) and Miguel Servet tenure track program (CP21/00096) of the ISCIII-Ministry of Science and Innovation (Spain), respectively awarded on the 2019 and 2021 calls under ISCIII-Health Strategy Actions [These grants are co-funded with European Union ERDF Funds (European Regional Development Fund)]. Cristina Lorca's PhD is funded by the Regional Ministry of Science, Universities and Innovation of the Community of Madrid and the European Social Fund for the recruitment of pre-doctoral researchers (PEJD-2019 PRE/BIO-16475)