Objective: To investigate the expression of miR-212 and miR-132 in the serum of patients with primary liver cancer and their targeted regulation of GP73. Methods: The patients with liver cancer, chronic hepatitis B, or liver cirrhosis who were hospitalized in Taizhou People’s Hospital from January 2015 to December 2016 were enrolled, and healthy volunteers were also enrolled as controls. Quantitative real-time PCR was used to measure the serum levels of miR-212 and miR-132, and the association between the expression of serum miR-212 and miR-132 and the clinicopathological features of patients with liver cancer was analyzed. A Spearman’s rank correlation analysis was used to analyze the correlation between serum miR-212/miR-132 and GP73. Western blot was used to measure the protein expression of GP73, and MTT assay was used to measure the survival rate of cells. The Levene’s homogeneity of variance test was used for data analysis. The independent samples t-test was used for comparison of means between two samples, and ANOVA was used for comparison of means between multiple samples. Results: A total of 90 patients with liver cancer, 60 with chronic hepatitis B, 68 with liver cirrhosis, and 100 healthy volunteers were enrolled. The relative expression levels of miR-212 and miR-132 in serum were 0.046 6 ± 0.024 7 and 0.005 9 ± 0.003 0 in the patients with liver cancer, 0.979 7 ± 0.259 5 and 1.001 8 ± 0.249 9 in the healthy volunteers, 0.588 2 ± 0.216 5 and 0.345 7 ± 0.233 8 in the patients with hepatitis, and 0.313 8 ± 0.153 3 and 0.080 1 ± 0.042 66 in the patients with liver cirrhosis. Compared with the normal controls, all patients had significant reductions in the expression of serum miR-212 (t = 10.26, 20.86, and 35.80, all P < 0.01) and miR-132 (t = 16.55, 36.09, and 39.85, all P < 0.01). In the patients with liver cancer, the relative expression of miR-212 and miR-132 was negatively correlated with alpha-fetoprotein (miR-212: t = -4.46, P < 0.01; miR-132: t = -4.83, P < 0.01), TNM stage (miR-212: t = 6.569, P < 0.01; miR-132: t = 7.31, P < 0.01), degree of tumor differentiation (miR-212: t = 5.268, P < 0.01; miR-132: t = 5.914, P < 0.01), and presence of portal vein tumor thrombus (miR-212: t = 5.16, P < 0.01; miR-132: t = 3.681, P < 0.01), while it was not correlated with tumor size (miR-212: t = 0.687, P > 0.05; miR-132: t = 0.887, P > 0.05). In addition, serum miR-212 and miR-132 were negatively correlated with GP73 in the patients with liver cancer (miR-212: r_s = -0.709, P < 0.01; miR-132: r_s = -0.877, P < 0.01). Overexpression of miR-212 or miR-132 in HepG2 cells significantly inhibited the activity and expression of 3’-UTR, and interference of miR-212 or miR-132 significantly increased the activity and expression of 3’-UTR in GP73. Overexpression of GP73 reversed the reduction in survival rate of hepatoma cells induced by the overexpression of miR-212 or miR-132. Conclusion Patients with liver cancer have a significant reduction in the expression of miR-212 and miR-132 in serum, which is closely associated with the development, progression, and metastasis of liver cancer, and miR-212 and miR-132 in hepatoma cells inhibit the growth of liver cancer by targeted regulation of GP73 expression.