Codeine is one of the most commonly used opioid analgesics. Significant codeine-related morbidity and mortality prompted regulatory responses, with the up-scheduling of codeine combination analgesics to prescription-only medicines implemented in Australia in February 2018. This study investigated the impact of codeine up-scheduling on the number of codeine and other (non-codeine) prescription opioid-related emergency department (ED) presentations in a large metropolitan tertiary hospital. Clinical features of these presentations were also examined. Interrupted time series analyses assessed monthly changes in ED presentations from June 2016 – November 2019. In the month immediately after up-scheduling, there was a significant reduction of 3.97 codeine-related presentations (B = -3.97, p = 0.022), indicating a 29.66% level change, followed by a significant change in trend to fewer monthly codeine-related presentations (B = -0.38, p = 0.005). Non-codeine prescription opioid-related (B = -1.90, p = 0.446) and ED presentations overall (B = -118.04, p = 0.140) remained unchanged immediately post-up-scheduling, with a significant change in trend from upward to downward for non-codeine (B = -0.76; p = 0.002) and ED presentations overall (B = -19.34, p = 0.022). A significant reduction of 4.58 (B = -4.58, p = 0.009) in codeine presentations involving subsequent hospital admission immediately post-up-scheduling was found; but no immediate reduction in codeine-related suicide-related overdoses, length of inpatient stay or re-presentations (ps > 0.0125; adjusted for multiple comparisons). Restricting supply of codeine to prescription-only may have resulted in less harmful codeine-related use in the community, without a corresponding immediate decrease in other opioid-related harms.