Congenital heart defects (CHD) are the most common major birth defects and one of the leading causes of death from congenital defects after birth. CHD can arise in pregnancy from the combination of genetic and non-genetic factors. The maternal immune activation (MIA) hypothesis is widely implicated in embryonic neurodevelopmental abnormalities. MIA has been found to be associated with the development of asthma, diabetes mellitus, and other diseases in the offspring. Given the important role of cardiac immune cells and cytokines in embryonic heart development, it is hypothesized that MIA may play a significant role in embryonic heart development. This review aims to stimulate further investigation into the relationship between MIA and CHD and to highlight the gaps in the knowledge. It evaluates the impact of MIA on CHD in the context of pregnancy complications, immune-related diseases, infections, and environmental and lifestyle factors. The review outlines the mechanisms by which immune cells and their secretome indirectly regulate the immuno-microenvironment of the embryonic heart by influencing placental development. Furthermore, the inflammatory cytokines cross the placenta to induce related reactions including oxidative stress in the embryonic heart directly. This review delineates the role of MIA in CHD and underscores the impact of maternal factors, especially immune factors, as well as the embryonic cardiac immuno-microenvironment, on embryonic heart development. This review extends our understanding of the importance of MIA in the pathogenesis of CHD and provides important insights into prenatal prevention and treatment strategies for this congenital condition. [GRAPHICS] .