In the United States, people who inject drugs intravenously (IVUs) often respond to opioid overdoses using intervention techniques that are not medically approved due to the unique legal, embodied, social and environmental risks IVUs, but not professionals, must navigate. Despite an unprecedented legislative shift towards harm reduction-informed overdose drug policy in the past decade, which help mitigate several risks complicating IVUs’ ability to respond by medically approved means, lay methods remain a common practice. While expert critiques of these methods are prevalent in medical and public health educational discourse, the unique cultural meanings and uses that unapproved methods hold among IVUs remain underacknowledged in professional medicine and underexamined in social scientific literature. Because medical and public health discourse discounts the methods without adequately addressing the unique risks IVUs contend with that professionals do not, IVUs are unable—not merely unwilling—to follow recommended medical practices. I argue that this medical lay knowledge must be recognized as an enduring cultural feature and an essential survival method among those who hold and apply this knowledge, and that the precarity of unapproved methods can be mitigated by policies and research practices that engage and validate, not erase and discredit, these alternative ways of knowing.