Due to high mortality rates and poor prognosis, liver injury remains one of the leading causes of mortality worldwide. Amounting evidence suggested that the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome, which promotes pro-interleukin-1β (pro-IL-1β) and pro-interleukin-18 (pro-IL-18) cleavage and maturation play a vital role in the occurrence and development of liver injury and liver disease. Mitochondrial dysfunction is a common co-occurring event in liver injury. Abnormal mitochondrial function has also been shown to be closely related to NLRP3 inflammasome activation. Currently, natural products have attracted the attention of researchers as potential therapeutic agents for liver injury and liver disease due to their less toxicity and multi-targeting advantages. A number of natural products have been discovered to prevent and treat liver injury by modulating the activation of NLRP3 inflammasome. In this review, we highlight the mechanisms involved in the regulation of NLRP3 inflammasome activation by mitochondria during liver injury and natural products that target mitochondrial function processes to prevent or treat liver injury. Our paper may shed insight into novel viewpoint and target for prevention and treatment of liver injury based on NLRP3 inflammasome.