Many harmful substances have been found in foods, such as heavy metals, organic pollutants, pesticides and antibiotics, and food additives are widely used in the industry. Recent studies showed that these substances could affect the composition and diversity of gut microbiota, which plays important roles in health and diseases of host. Thus, these substances could show toxicities through disrupting the homeostasis of gut microbiota. On the other hand, some dietary bioactive compounds were found to restore the dysbiosis of gut microbiota. Therefore, certain dietary natural products could relieve the toxicities of harmful substances on human beings via regulating gut microbiota. In this review, the influences of several harmful substances and additives on gut microbiota are summarized, and protective effects of dietary bioactive compounds are also discussed. It is hoped to provide a better understanding of dietary natural products to reduce toxicities of harmful substances on human beings by targeting gut microbiota. Considering wide existence of harmful substances and additives in foods, this topic would attract more attention in the future to protect human health. Gut microbiota plays a vital role in diseases and health based on human and most animal studies. Some gut microbes, such as Bifidobacterium and Lactobacillus, could synthesize various essential nutrients for human growth. In addition, some Bifidobacterium strains, Clostridium tyrobutyricum, and Lactobacillus paracasei, were associated with anti-inflammatory property. Moreover, Anaerostipes, Corynebacterium, Dorea, Roseburia, Ruminococcus, and Turicibacter, were also related to inflammation. Harmful substances, such as atrazine, polychlorinated biphenyl, and heavy metals, were mainly ingested through the contaminated water and foods, could disturb gut microbiota and be detrimental to health. Besides, gut microbiota dysbiosis was potentially caused by some food additives, which altered gut barrier and activated the immune response. On the other hand, some dietary natural products, such as melatonin, wheat bran, pectin, chlorogenic acid, and isoorientin, showed beneficial efficacy through restoring dysbiosis of gut microbiota caused by harmful substances. In the future, more attention should be paid to the exploration of more dietary plants and their components with gut microbiota regulatory effects in order to reduce the toxicities of harmful substances and protect human health. •The roles of gut microbiota in diseases and health are summarized.•The effects of contaminants and additives on gut microbiota are discussed.•The effects of bioactive compounds on gut microbiota dysbiosis are highlighted.•Gut microbiota is a promising target to reduce toxicities of harmful substance.