Public Health Officers (PHOs)’ experiences in reaction to the COVID-19 pandemic can be based on whether the PHO is active or passive regarding five experience aspects, including knowledge, understanding, opinion, participation, and practice. Therefore, this study’s objectives are to identify the types of experiences and analyse the predictors of proactive practical experiences in addressing the COVID-19 pandemic among PHOs in the southern region of Thailand. Methods: An explanatory mixed methods approach was used to collect data, through questionnaires and online in-depth interviews. This study was conducted from 4 August 2020 to 3 August 2021. Results: The results include 60 PHOs from 60 Primary Care Units in six provinces, with 41 (68.3%) females and an average age of 35.57 years (SD = 11.61). The PHOs’ knowledge, understanding, and participation experience aspects were mostly proactive rather than passive. The factors that significantly predicted proactive practical experiences included sex (ORadj = 1.52, 95% CI = 1.04–2.21), age (ORadj = 1.69, 95% CI = 1.16–2.48), married status (ORadj = 1.69, 95% CI = 1.16–2.48), education level (ORadj = 1.50, 95% CI = 1.02–2.20), and position for work (ORadj = 1.69, 95% CI = 1.16–2.48). The results of quantitative method were confirmed by 12 sub-themes of 8 PHOs’ experiences from qualitative method. Conclusions: The PHOs’ knowledge, understanding, opinion, and participation experiences were significant predictors of practical experience. Primary health care systems should promote proactive experiences in all four aspects to increase proactive practical experiences.