There is growing evidence of the beneficial health effects of omega-3 fatty acid (FAs) supplementation on gene expression of metabolic factors, but a summation of outcomes from randomized controlled trials (RCTs) is lacking. Our aim was to investigate the state of the evidence on the potential impacts of omega-3 FA oral intake on gene expression of factors related to inflammation and oxidative stress (IL-1, IL-8, Sirt-1 and TNF-α) and cardiometabolic parameters (LDLR, PPAR-gamma, adiponectin, Lp(a), and GLUT-1). Scopus, Web of Science, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched from inception until December 2020. RCTs which evaluated the effect of oral intake of omega-3 FA on gene expression of cardiometabolic risk factors were included. Data were extracted using STATA software and analyzed using a random effect model. The effect size is given in a standardized mean difference (SMD) and a 95% confidence interval (95% CI). The quality of the included RCTs was assessed by Cochrane tool and almost all studies had a fair quality. Thirteen trials were included in this systematic review. Current analysis indicated that omega-3 FA intake significantly up-regulated the PPAR-gamma (SMD: 1.05; 95% CI: 0.62, 1.48; I2 = 73.9%) and down-regulation of LDLR (SMD: −0.75; 95% CI: −0.38, −0.13; I2 = 77.8%) and IL-1(SMD: −0.89; 95% CI: −1.24, −0.54; I2 = 00.0%). However, these outcomes also indicate that omega-3 FA intake has no significant effect on the gene expression of adiponectin, GLUT-1, Lp(a), IL-8, Sirt-1 and TNF-α. This analysis suggests that omega-3 FA intake may improve gene expression of PPAR-gamma, LDLR and IL-1. However, large well-designed, and long-duration RCTs are still required to clarify the effect of omega-3 FA intake on the expression of critical factors related to inflammation, oxidative stress, and cardiometabolic parameters codifying genes.