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MicroRNA-122 (miR-122) is a liver-specific microRNA that maintains liver homeostasis by regulating lipid metabolism, cell differentiation and viral infections in vertebrates. In clinics, hepatocellular carcinoma (HCC) patients with low miR-122 levels are usually associated with poor prognosis, implying miR-122 functions as a tumor suppressor. This notion is supported by the phenotypes of miR-122 genetic knockout (KO) mouse that develops spontaneous hepatitis, steatosis, fibrosis and HCC with age. Although several studies have shown the importance of miR-122 in maintaining liver homeostasis, the mechanisms by which loss of miR-122 contributes to these liver pathological processes remains largely unknown. In the current study, we explored the role of miR-122 in regulating liver inflammation and fibrosis by combining molecular, biochemical, and bioinformatic analysis. We demonstrated that the increased expression of the chemokine CCL2 in the liver is one of the causes of liver inflammation upon deprivation of miR-122. Blocking CCL2 using specific neutralizing antibody (CCL2 nab) ameliorates liver inflammation and tumorigenesis through decreasing the population of CD11b+/Gr1+ cells and their corresponding downstream pathways such as the IL-6-Stat3-cMYC axis and TNF-alpha-NF-kappaB axis. Along with the shrinking tumors in the CCL2 nab treated liver, CCL2 nab also activated natural killer (NK) cells and increased their cytotoxicity toward tumor cells. Besides its robust role in inhibiting liver inflammation and HCC tumors, miR-122 also has a strong anti-fibrosis function. Analyzing database that contained both clinical and expression profiles of liver cirrhosis patients revealed downregulation of miR-122 in the cirrhotic liver tissues compared to normal livers. Ectopic expression of miR-122 in LX-2, an immortalized human hepatic stellate cell (HSC) cell line, reduced cell proliferation and fibrotic gene expressions. Moreover, co-culture of miR-122 expressed HCC cells with miR-122 non-expressing LX-2 cells resulted in miR-122 expression and reduced expression of fibrotic genes, suggesting extracellular miR-122 could be delivered from hepatocytes to HSCs. We next searched hepatic microarray and RNA-seq data in the wild type and miR-122 KO mice to identify miR-122 downstream molecules that promote liver fibrosis. We focused on genes that have been shown to be pro-fibrotic and overexpressed in the human fibrotic livers as well as in the miR-122 KO livers. One such fibrotic gene, B cell lymphoma 2 (BCL2), was found to be upregulated in the HBV- and HCV-infected cirrhotic livers compared to the normal livers (data retrieved from GEO and EMBL-EBI). Besides, BCL2 expression is significantly increased in the mouse livers depleted of miR-122 as demonstrated by microarray, RNA-seq and immunoblot analysis. Venetoclax, an FDA approved BCL2 inhibitor for chronic leukemia lymphoma (CLL), inhibited LX-2 cell proliferation and expression of pro-fibrotic markers, and reduced liver fibrosis in the miR-122 KO mice. Collectively, this study provides a new mechanistic insight on miR-122 mediated suppression of liver inflammation, fibrosis, and HCC. Moreover, our data demonstrated that targeting miR-122 downstream molecules (e.g. CCL2, and BCL2) could be effective in blocking spontaneous liver inflammation, fibrosis and HCCs developed in miR-122 depleted livers.