From January 2020 to December 2022, over 139,740 drug overdose deaths occurred in the U.S., with nearly 70% involving synthetic opioids, primarily illegally manufactured fentanyl (IMF) and fentanyl analogs. The percentage of overdose deaths with evidence of smoking increased significantly, from 13.3% to 23.1%, while the percentage with evidence of injection decreased from 22.7% to 16.1%. Smoking became the most common route of drug use in overdose deaths by 2022. This shift was observed across all U.S. regions, with the Midwest and West seeing the highest increases in smoking as the primary route. Among deaths involving only IMFs, the percentage with evidence of smoking increased by 78.9%, while injection decreased by 41.6%. Similar trends were seen in deaths involving both IMFs and stimulants. The transition from injecting heroin to smoking IMFs is likely a key factor in these changes. Smoking carries substantial overdose risk due to rapid drug absorption, but it may be perceived as less risky than injection. Public health efforts should focus on harm reduction services tailored to non-injection routes, including smoking, to reduce overdose deaths. Syringe services programs and other harm reduction strategies are crucial for addressing the risks associated with drug use. Limitations include the lack of data on some routes and the potential for underestimating non-injection routes. Overall, expanding harm reduction services and public health messaging to address the risks of smoking and other non-injection routes is essential for reducing drug overdose deaths.From January 2020 to December 2022, over 139,740 drug overdose deaths occurred in the U.S., with nearly 70% involving synthetic opioids, primarily illegally manufactured fentanyl (IMF) and fentanyl analogs. The percentage of overdose deaths with evidence of smoking increased significantly, from 13.3% to 23.1%, while the percentage with evidence of injection decreased from 22.7% to 16.1%. Smoking became the most common route of drug use in overdose deaths by 2022. This shift was observed across all U.S. regions, with the Midwest and West seeing the highest increases in smoking as the primary route. Among deaths involving only IMFs, the percentage with evidence of smoking increased by 78.9%, while injection decreased by 41.6%. Similar trends were seen in deaths involving both IMFs and stimulants. The transition from injecting heroin to smoking IMFs is likely a key factor in these changes. Smoking carries substantial overdose risk due to rapid drug absorption, but it may be perceived as less risky than injection. Public health efforts should focus on harm reduction services tailored to non-injection routes, including smoking, to reduce overdose deaths. Syringe services programs and other harm reduction strategies are crucial for addressing the risks associated with drug use. Limitations include the lack of data on some routes and the potential for underestimating non-injection routes. Overall, expanding harm reduction services and public health messaging to address the risks of smoking and other non-injection routes is essential for reducing drug overdose deaths.