The animal-based pharmacognosy has become a central science in the 21 st century, which represents a summarization of the conventional old knowledge of medicines and modern drug discovery. Using such models as rodents, zebrafish, and Caenorhabditis, the pharmacological activities of plant-derived active ingredients have been confirmed, indicating the use of active ingredients against inflammations, neuroprotective properties, antioxidant, antidiabetic characteristics, and wound-healing properties. High-end technological methodologies, such as assay of toxicity, behavioral analysis and disease-related models, have promoted both efficacy and safety analyses, whereas the current technological tools, such as LC-MS/MS, network pharmacology, and computational modeling, have increased accuracy, repeatability, and elucidation of the mechanism. Though interspecies variation, absence of standardization of extraction procedures and ethical issues remain a challenge in the field of animal-based pharmacognosy, it has been a revolutionary step in merging ethnomedicine and modern-day biomedical research. New paradigms, like high-throughput screening and omics methods, as well as alternative platforms, e.g., organ-on-chip systems are transforming the field, thereby providing more ethical, accurate, and translationally relevant practices. Combining or integrating the traditional wisdom and modern innovative approach, animal-based pharmacognosy can support sustainable drug discovery pipelines and offer immense opportunity in meeting the global health challenges.