The present study investigates the mediating roles of psychological inflexibility and differential coping strategies on perceived stress and post-traumatic symptoms and growth in the context of COVID-19. Study one recruited 662 participants (54.8% women; Mage = 40.64 years, SD = 13.04) who completed a cross-sectional questionnaire. It was proposed that orientation to the problem, avoidance strategies, psychological inflexibility, and positive attitude were mediators for the positive association between perceived stress and PTSD symptoms. The fit indices for the path model were excellent: CFI = 0.977, TLI = 0.950, RMSEA = 0.057 [90%CI = 0.043–0.081], and SRMS = 0.042. Gender and stressful events encountered had indirect effects on the endogenous variables. In study two, 128 participants (57.8% women; Mage = 42.30, SD = 12.08) were assessed for post-traumatic growth one year later. Psychological inflexibility and orientation acted as mediators between perceived stress and PTSD symptoms. Furthermore, a novel path model was constructed in which psychological inflexibility and orientation to the problem as mediators for perceived stress and PTSD symptoms. The indices for the path model were excellent: CFI = 0.99, TLI = 0.97, RMSEA = 0.055 [90%CI = 0.001–0.144], and SRMS = 0.49. Furthermore, PTSD symptoms, psychological inflexibility, and orientation to the problem predicted post-traumatic growth. Specifically, both orientation to the problem (β = .06 [90%CI: .01;.13]) and psychological inflexibility (β = .14 [90%CI: .08;.26]) had an indirect effect on post-traumatic growth. Overall, these results significantly contribute to the literature as orientation to the problem positively predicted PTSD symptoms and post-traumatic growth one year later while psychological inflexibility predicted PTSD symptoms and less post-traumatic growth one year later. These results underline the importance of assessing both symptomology and psychological growth to determine adaptive coping strategies in specific contexts.