Introduction Deaths have increased, and prescription medications are involved in a significant percentage of deaths. Emergency department (ED) changes to managing acute pain and prescription drug monitoring programs (PDMPs) can impact the potential for abuse. Methods We analyzed the impact of a series of quality improvement initiatives on the opioid prescribing habits of emergency department physicians and advanced practice providers. We compared historical prescribing patterns with those after three interventions: 1) the implementation of a PDMP, 2) clinician education on alternatives to opioids (ALTOs), and 3) electronic health record (EHR) process changes. Results There was a 61.8% decrease in the percentage of opioid-eligible ED discharges that received a prescription for an opioid from 19.4% during the baseline period to 7.4% during the final intervention period. Among these discharges, the cumulative effect of the interventions resulted in a 17.3% decrease in the amount of morphine milligram equivalents (MME) prescribed per discharge from a mean of 104.9 MME/discharge during the baseline period to 86.8 MME/discharge. In addition, the average amount of MME prescribed per discharge became aligned with recommended guidelines over the intervention periods. Conclusions Initiating a PDMP and instituting an aggressive ALTO program along with EHR-modified process flows have cumulative benefits in decreasing MME prescribed in an acute ED setting.