Opioid-related harm is a critical patient safety priority. This case control study examined the risk of opioid overdose among children whose mothers were prescribed either opioids or nonsteroidal anti-inflammatory agents in the prior year. The cases were children aged 10 or younger who were hospitalized or died from opioid overdose, and the controls were children of the same age without overdose. Compared to the children without overdose, those who were hospitalized or died were more likely to have a mother who was prescribed opioids. Antidepressant prescription was also more common among mothers of children who experienced opioid overdose. The authors recommend specific practices for safe opioid use, including prescription of smaller quantities and secure storage of medications, which prior studies demonstrate are not yet routine. This study emphasizes the urgent need to enhance the safety of outpatient opioid use.