Background: Despite the indications suggested in the world to contain the COVID-19 pandemic, the report of psychopathological problems due to SARSCoV-2 infection, as well as morbidity and mortality, increase day after day. Objective: To identify if some psychosocial factors, in interaction with knowledge about symptoms and forms of contagion, can predict preventive behaviors (specific and universal) of COVID-19. M aterials and M ethod: This study was developed with a Colombian sample (n = 788, X = 32.98 years, SD 12.01). The online information was obtained using the EEP-10, EAG, LOT-R, APGAR and ERQ questionnaires for psychological variables, as well as an Ad-Hoc questionnaire about perceptions and protective behaviors against COVID-19, evaluated and accepted by three experts; the reports were analyzed using non-parametric statistics and linear regressions. Results: Knowledge about symptoms and contagion, positive reappraisal, and optimism, in interaction, predict specific contagion prevention practices (R2 = 0.05, p = 0.001), and together with reported stress and their perception of control predict universal healthy behaviors (R2 = 0.11, p = 0.001). Conclusion: It is necessary to strengthen evidence-based interventions to improve the psychosocial factors underlying the described healthy behaviors and the reduction of the probability of developing mental health disorders. © 2022 Academia Nacional de Medicina. All rights reserved.