In March 2020, British Columbia, Canada, became the first jurisdiction globally to launch a large-scale provincewide safer supply policy. The policy allowed individuals with opioid use disorder at high risk of overdose or poisoning to receive pharmaceutical-grade opioids prescribed by a physician or nurse practitioner, but to date, opioid-related outcomes after policy implementation have not been explored. To investigate the association of British Columbia's Safer Opioid Supply policy with opioid prescribing and opioid-related health outcomes. This cohort study used quarterly province-level data from quarter 1 of 2016 (January 1, 2016) to quarter 1 of 2022 (March 31, 2022), from British Columbia, where the Safer Opioid Supply policy was implemented, and Manitoba and Saskatchewan, where the policy was not implemented (comparison provinces). Safer Opioid Supply policy implemented in British Columbia in March 2020. The main outcomes were rates of prescriptions, claimants, and prescribers of opioids targeted by the Safer Opioid Supply policy (hydromorphone, morphine, oxycodone, and fentanyl); opioid-related poisoning hospitalizations; and deaths from apparent opioid toxicity. Difference-in-differences analysis was used to compare changes in outcomes before and after policy implementation in British Columbia with those in the comparison provinces. The Safer Opioid Supply policy was associated with statistically significant increases in rates of opioid prescriptions (2619.6 per 100 000 population; 95% CI, 1322.1-3917.0 per 100 000 population; P < .001) and claimants (176.4 per 100 000 population; 95% CI, 33.5-319.4 per 100 000 population; P = .02). There was no significant change in prescribers (15.7 per 100 000 population; 95% CI, -0.2 to 31.6 per 100 000 population; P = .053). However, the opioid-related poisoning hospitalization rate increased by 3.2 per 100 000 population (95% CI, 0.9-5.6 per 100 000 population; P = .01) after policy implementation. There were no statistically significant changes in deaths from apparent opioid toxicity (1.6 per 100 000 population; 95% CI, -1.3 to 4.5 per 100 000 population; P = .26). Two years after its launch, the Safer Opioid Supply policy in British Columbia was associated with higher rates of safer supply opioid prescribing but also with a significant increase in opioid-related poisoning hospitalizations. These findings will help inform ongoing debates about this policy not only in British Columbia but also in other jurisdictions that are contemplating it.