Introduction: During the COVID-19 pandemic, drug overdose deaths increased significantly, providing a potential cohort of donor organs. However, graft failure and mortality rates among those receiving organs from donors who died from drug overdose related to the pandemic have not previously been assessed. We compared graft failure and mortality up to one year after transplant of those receiving a kidney or liver pre-pandemic and during the pandemic. Methods: A retrospective analysis between pre-pandemic (1 January 2018 to 31 December 2019) and pandemic (1 January 2020 to 31 December 2021) periods was performed using the United Network for Organ Sharing (UNOS) database. Recipients aged 17 or below and those with multiple-organ transplants were excluded. ANOVA tests for continuous variables and Chi-squared or Fisher’s exact tests were utilized to compare graft failure and mortality of transplant outcomes. The Kaplan–Meier (KM) Product Limit method was employed to estimate transplant outcomes and survival curves. For graft failure analysis, graft survival was the endpoint. For survival analysis, recipient death was the endpoint. Multivariate Cox regression analyses were performed for suspected risk factors (i.e., recipient and donor demographics, clinical factors, donor characteristics, including cause of death and transplant-related variables). Results: Pandemic-era kidney recipients experienced significantly higher one-year graft failure and mortality than pre-pandemic recipients. Liver recipients also had higher one-year graft failure during the pandemic, but no statistically significant change in mortality. ODD liver recipients had a 22% reduction in one-year graft failure compared with other causes of death (p = 0.009). ODD kidneys were not inferior to non-ODD donors and were independently protective in several period-stratified comparisons. Conclusions: Pandemic-era recipients experienced worse one-year outcomes than pre-pandemic recipients across both organs, driven primarily by kidney graft failure and mortality. Drug overdose donor organs were not inferior to other donor sources in either period and were independently protective in several period-stratified comparisons. These data support continued and expanded use of drug overdose donor organs, including during periods of systemic strain.