The sea is a vast ecosystem that has remained primarily unexploited and untapped, resulting in numerous organisms. Consequently, marine organisms have piqued the interest of scientists as an abundant source of natural resources with unique structural features and fascinating biological activities. Marine macrolide is a top-class natural product with a heavily oxygenated polyene backbone containing macrocyclic lactone. In the last few decades, significant efforts have been made to isolate and characterize macrolides' chemical and biological properties. Numerous macrolides are extracted from different marine organisms such as marine microorganisms, sponges, zooplankton, molluscs, cnidarians, red algae, tunicates, and bryozoans. Notably, the prominent macrolide sources are fungi, dinoflagellates, and sponges. Marine macrolides have several bioactive characteristics such as antimicrobial (antibacterial, antifungal, antimalarial, antiviral), anti-inflammatory, antidiabetic, cytotoxic, and neuroprotective activities. In brief, marine organisms are plentiful in naturally occurring macrolides, which can become the source of efficient and effective therapeutics for many diseases. This current review summarizes these exciting and promising novel marine macrolides in biological activities and possible therapeutic applications.