Medicinal chemists and pharmacognosists have relied on terrestrial sources for bioactive phytochemicals to manage and treat disease conditions. However, minimal interest is given to sea life, especially macroalgae and their inherent phytochemical reserves. Phlorotannins are a special class of phytochemicals mainly predominant in brown algae of marine and estuarine habitats. Phlorotannins are formed through the polymerization of phloroglucinol residues and derivatives via the polyketide (acetate–malonate) pathway. Studies over the past decades have implicated phlorotannins with several bioactivities, including anti-herbivory, antioxidants, anti-inflammatory, anti-microbial, anti-proliferative, anti-diabetic, radio-protective, adipogenic, anti-allergic, and anti-human immunodeficiency virus (anti-HIV) properties. All these activities are reflected in their applications as nutraceuticals and cosmeceutical agents. This article reviews the chemical composition of phlorotannins, their biological roles, and their applications. Moreover, very few studies on phlorotannin bioavailability, safety, and toxicity have been thoroughly reviewed. The paper concludes by suggesting exciting research questions for further studies.