Currently, it is unknown whether fatty acids (FAs) and primary liver cancer (PLC) are associated. The cause-effect association was established using a two-sample Mendelian randomization (MR) study. Eligible single nucleotide polymorphisms were selected as instrumental variables from six FAs genome-wide association studies. The outcome involved a total of 260,428 subjects and was a summary of genetic data on PLC from FinnGen biobanks. The principal method inverse variance weighted (IVW) and several other analytical approaches (MR-Egger, Weighted Median, and Maximum likelihood) were tested to determine the causal relationship between different FAs and PLC. Furthermore, sensitivity analyses were performed to determine the stability of the results. The two-sample MR analysis revealed a negative causal relationship between omega-3 FAs and PLC. It was discovered that an increase in each standard deviation (0.53 mmol/L; SD: 0.22) in the genetic levels of omega-3 FAs reduced the risk of PLC by 62.1% through the IVW method [odd ratio: 0.379; 95% confidence interval (0.176, 0.816)]. Nevertheless, other FAs were not statistically correlated with PLC. Additionally, no pleiotropy was found between the two. According to the MR study, consuming omega-3 FAs may help prevent PLC.