ImportanceLayperson-administered naloxone (LAN) is a powerful but incompletely characterized intervention to prevent opioid-related overdose mortality. LAN trends are relevant to policy and strategic planning in naloxone distribution initiatives.ObjectiveTo assess the 2-year LAN trend for persons in the United States receiving naloxone during emergency medical services (EMS) activations.Design, Setting, and ParticipantsThis retrospective cross-sectional study was conducted in the United States from June 2020 to June 2022 among 65 621 195 EMS activations from 911 responses, EMS standbys, or when EMS crews functioned in an ambulance intercept role or during mutual aid to another ambulance response. Activations within health care settings and interfacility or medical transports were excluded. Data are from the National Emergency Medical Services Information System (NEMSIS), the national EMS patient care record database. From June 2020 to June 2022, NEMSIS included more than 96 million EMS activations from nearly 14 000 agencies across 54 states and territories.ExposuresEMS clinician–reported LAN.Main Outcome and MeasuresThe primary outcome was the trend of receiving LAN, measured by EMS clinician documentation.ResultsFrom June 2020 to June 2022, EMS reported 744 078 patients receiving naloxone, with 24 990 (3.4%) involving LAN. Patients were predominantly male (17 331 [69.4%]) and had a median (IQR) age of 42 (31-56) years, with the majority treated in urban homes or residences (21 692 [86.8%] urban; 13 223 [52.9%] in-home or residence). Of the total naloxone recipients, 243 985 patients (32.8%) had suspected drug overdose documentation as either the primary or secondary impression. Overall, the percentage change in naloxone administration rates decreased 6.1% over the study period (from 1140.1 [95% CI, 1135.1-1145.1] per 100 000 EMS activations to 1070.1 [95% CI, 1064.9-1075.3] per 100 000 EMS activations), while the percentage change of persons receiving LAN increased 43.5% (from 30.0 [95% CI, 29.2-30.8] per 100 000 EMS activations to 43.1 [95% CI, 42.0-44.1] per 100 000 EMS activations).Conclusions and RelevanceIn this cross-sectional study, the LAN rate increased from June 2020 to June 2022 as reported in the national EMS database. These findings help inform policies and practices aimed at mitigating the devastating impacts of the opioid epidemic and saving lives. Novel public health strategies are needed to measure the effects of this intervention nationally, evaluate approaches to expand naloxone distribution, and address naloxone usage barriers.