Abstract: Marine natural products (MNPs) comprise structurally diverse molecules from marine algae, invertebrates, vertebrates, microorganisms, and multi-partner holobionts and they continue to provide important starting points for therapeutic innovation. However, conventional MNP discovery has long relied on empirical sampling and serendipitous isolation, making the efficient discovery of novel, bioactive, and mechanistically interpretable molecules challenging. Recent advances in marine chemical ecology and emerging technologies now support an evidence-based paradigm that links source biology, ecological function, chemical novelty, spatial distribution, bioactivity, and molecular targets. This review summarizes recent advances in the discovery of MNPs with therapeutic potential across the full range of marine biological sources. We first discuss how environmental context, predator–prey interactions, tissue localization, and host–microbiome associations can guide source selection and biosynthetic-source tracing. We then examine MS- and NMR-guided dereplication, AI-assisted annotation, mass spectrometry imaging, and genome mining as tools for mapping and prioritizing marine chemical space. Finally, we discuss phenotype-based bioactivity screening, AI-assisted activity prediction, and chemical-biology strategies for target identification and mechanism-of-action validation. By linking these stages, MNP research can move from empirical collection and blind isolation toward a more systematic, data-informed, and mechanism-oriented discovery framework.