Opioid-related deaths have transitioned over the past 15 years, beginning with a steady increase in the incidence of fatal prescription overdoses, followed by a dramatic increase in deaths caused by illicit opioids, namely heroin and fentanyl. These trends in drug-related deaths are identified by medical examiners and coroners who serve an important role in public health surveillance. Medicolegal death investigators, being first responders, often recognize spates of drug-related deaths in real time. While few jurisdictions are unaffected by the epidemic, some medicolegal death investigators may have less experience detecting fatal opioid overdoses. This review will outline many of the medical, behavioral, and physical indicators of a deadly prescription or illicit opioid overdose. All aspects of a thorough medicolegal death investigation will be discussed, including the proper documentation of the scene and evidence handling. Investigative questions and follow-up procedures will also be reviewed.