Aging is associated with changes in the immune system and the gut microbiota. Immunosenescence may lead to a low-grade, sterile chronic inflammation in a multifactorial and dynamic way, which plays a critical role in most age-related diseases. Age-related changes in the gut microbiota also shape the immune and inflammatory responses. Nutrition is a determinant of immune function and of the gut microbiota. Immunonutrion has been regarded as a new strategy for disease prevention and management, including many age-related diseases. However, the understanding of the cause-effect relationship is required to be more certain about the role of immunonutrition in supporting the immune homeostasis and its clinical relevance in elderly individuals. Herein, we review the remarkable quantitative and qualitative changes during aging that contribute to immunosenescence, inflammaging and microbial dysbiosis, and the effects on late-life health conditions. Furthermore, we discuss the clinical significance of immunonutrition in the treatment of age-related diseases by systematically reviewing its modulation of the immune system and the gut microbiota to clarify the effect of immunonutrition-based interventions on the healthy aging.