The rapid advancement of biomedical technologies and the application of novel treatment methods—ranging from gene therapy and regenerative medicine to specialized pharmaceutical interventions and surgeries lacking established clinical guidelines—have confronted legal systems with a fundamental challenge in defining the scope of criminal law. The core of this challenge lies in the absence of a “customary standard of care”; a criterion which, in traditional civil and criminal law, is considered the primary indicator for distinguishing between error and permissible conduct. This research investigates the foundations and limits of “physician criminal liability in novel treatments lacking standard protocols.” The central question of this paper is how legal systems can draw a boundary between “life-saving therapeutic innovations” and “criminal negligence.” Using a comparative and descriptive-analytical approach, while examining judicial precedents in the United States, international bioethics statements (such as the Declaration of Helsinki), and the provisions of the Islamic Penal Code of Iran, this study tests the hypothesis that “clinical innovation” is not inherently criminal in nature. Criminal liability for a physician arises only upon the establishment of gross negligence, deviation from scientific standards, and the violation of prior obligations. The findings of this research indicate that the evaluation criterion for interventions lacking protocols must be based on the “risk-benefit balance doctrine” and the “theory of last resort.” Furthermore, the article explains that under Iranian law, obtaining informed, enhanced consent and compliance with government regulations, alongside proving the absence of negligence, constitute the pillars of a physician’s defense.