Dry eye disease (DED) is a local ocular surface disease caused by a multitude of factors and involves multiple interacting mechanisms. The prevalence of DED is rapidly increasing in the modern aged society, and it is considered a major ocular condition with a high prevalence among the elderly, who frequently have multiple comorbidities. Systemic medical conditions can have a negative impact on ocular health. In addition, a variety of systemic drugs can also induce DED via multiple mechanisms. The adequate management of general systemic diseases may control DED progression. Furthermore, according to the antiaging theory, an appropriate lifestyle intervention is preventive for both DED and general systemic disease. In this article, we focus on systemic health and DED to provide a broad overview of the association between systemic health, particularly in relation to aging, and DED. Ophthalmologists should carefully interview patients with DED regarding systemic comorbidities to deliver optimal treatment. A systemic approach, including the use of supplements and lifestyle intervention, should be used in addition to conventional local treatment.