The aim was to (i) compare the rates of perceived stress, post-traumatic stress symptoms (PTSS) and other potential correlates (i.e., resilience, social support, coping strategies, and loneliness) in the general population between the two COVID-19 lockdowns in Greece and (ii) explore risk and protective factors of PTSS. Online data were collected amid the first (timepoint 1-T1) and second lockdown (timepoint 2-T2) by 1009 and 352 participants, respectively. The PTSD Checklist for DSM-5 and the Perceived Stress Scale measured levels of PTSS and perceived stress. The Brief Resilience Scale, the COPE, the revised UCLA Loneliness Scale, and the ENRICHD Social Support Instrument measured resilience, coping strategies, loneliness, and social support, respectively. Higher levels of PTSS and perceived stress were reported during T2, compared to T1. Clinically significant levels of PTSS were presented by 26.1% and 35.5% of the participants during T1 and T2, respectively. Higher levels of loneliness and use of maladaptive coping strategies and lower levels of social support, resilience and use of adaptive coping strategies were also found. During both lockdowns, PTSS were predicted by perceived stress, loneliness, reduced resilience and the coping strategies of denial and self-blame. PTSS were associated with younger age, female gender, being single, not having children, and the evaluation of the pandemic as a crisis. The findings highlight the significant public mental health concerns during the COVID-19 lockdowns. Understanding the risk and protective factors against PTSS and focusing on vulnerable populations should be prioritized by the governments worldwide in the development of evidence-based interventions.