Abstract Background Non-pharmaceutical interventions (NPIs) decrease COVID-19 transmission. We identified behavioral factors that affected NPI adherence according to Normalization Process Theory (NPT) in medical students, travel seekers, and people with substance use disorder using reflective model measurement, which previously had not been conducted. Public health officials should consider factors that influence adherence to create preventive strategies for COVID-19. Methods In a cross-sectional design, medical students and people with substance use disorders in treatment comprised a probabilistic sample, and travelers and COVID-19 suspected persons comprised a convenience sample. Participants were from Split-Dalmatia County (n = 656) in the Mediterranean and consented to self-administered surveys in 02/2021. Sociodemographic data, locus of control (LoC), and moral behavior were collected. Partial least squares structural equation modeling (PLS-SEM) was used to measure reflective assessment of NPI adherence according to NPT. Results PLS-SEM reflective model assessment provided two-group specific factors in inverse relationships which determined NPI adherence with excellent goodness of fit (χ2=1.292, df = 1; p = 0.297). Significant negative factors covariance estimate (-0.716) revealed an increase in adherence to the first factor, NPIs and internal LoC [0.640], as the second factor, age (≤25) and highest education level (1.362), decreased. LoC was the mechanism by which sex (MLsex=-0.017, SE = 0.007, p < 0.016) and being a student or person with substance use disorder (MLgroup=-0.008, SE = 0.003, p = 0.015) showed indirect effect on NPI adherence. Conclusions Students and people with substance use disorders more adhered to NPIs. Higher-educated younger adults with a tendency toward external LoC facilitated the normalization. Public health interventions could encourage these subgroups to act as promoters to increase NPI adherence in similar settings. Key messages • COVID-19 non-pharmaceutical interventions and psychological factors of students and people with substance abuse disorder influenced adherence. Targeted interventions could promote adherence. • Public health officials should consider that preventive strategies may be more effective in highly educated adults younger than 25 years of age.