The identification of drugs in blood plays a central role in clinical diagnostics, forensic investigations, therapeutic monitoring, and toxicological assessments. As global patterns of medication use, substance abuse, and exposure to novel psychoactive substances (NPS) continue to evolve, the demand for rapid, sensitive, and reliable analytical techniques has grown substantially. This review presents an extensive evaluation of contemporary blood drug detection methods, ranging from traditional immunoassays and chromatographic techniques to advanced mass spectrometry platforms, biosensors, and microfluidic technologies. The principles, workflow, advantages, and limitations of each method are discussed in detail. Furthermore, this article explores real-world applications in clinical medicine, emergency care, forensic toxicology, legal investigations, workplace compliance testing, and public health surveillance. Special emphasis is given to emerging innovations such as artificial intelligence-driven interpretation, point-of-care diagnostics, portable spectroscopy, and nanotechnology-based tools, which are reshaping modern drug-testing paradigms. By providing a comprehensive overview, this review highlights the progress, challenges, and future directions of blood drug detection to support scientific research, improve diagnostic accuracy, and guide evidence-based decision-making.