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<i>Ganoderma lucidum</i> is traditionally used to prevent and treat some diseases such as liver disorders, hypertension, insomnia, diabetes, and cancer. <i>G. lucidum</i> spore extracts are also reported to share similar bioactivities as extracts from its other parts. However, there is no systematic review that elucidates its pharmacological effect. Our aim is to comprehensively summarise current evidence of <i>G. lucidum</i> spore extracts to clarify its benefits to be applied in further studies. We searched five primary databases: PubMed, Virtual Health Library (VHL), Global Health Library (GHL), System for Information on Grey Literature in Europe (SIGLE), and Google Scholar on September 13, 2021. Articles were selected according to inclusion and exclusion criteria. A manual search was applied to find more relevant articles. Ninety studies that reported the pharmacological effects and/or safety of <i>G. lucidum</i> spores were included in this review. The review found that <i>G. lucidum</i> spore extracts showed quite similar effects as other parts of this medicinal plant including anti-tumor, anti-inflammatory, antioxidant effects, and immunomodulation. <i>G. lucidum</i> sporoderm-broken extract demonstrated higher efficiency than unbroken spore extract. <i>G. lucidum</i> extracts also showed their effects on some genes responsible for the body's metabolism, which implied the benefits in metabolic diseases. The safety of <i>G. lucidum</i> should be investigated in depth as high doses of the extract could increase levels of cancer antigen (CA)72-4, despite no harmful effect shown on body organs. Generally, there is a lot of potential in the studies of compounds with pharmacological effects and new treatments. Sporoderm breaking technique could contribute to the production of extracts with more effective prevention and treatment of diseases. High doses of <i>G. lucidum</i> spore extract should be used with caution as there was a concern about the increase in CA.