Background: Previous studies showed several associations between physical and mental health dimensions and well-being. This study aims to examine a complex path model explaining the life satisfaction of university students from Poland and Ukraine during the second wave of the COVID-19 pandemic. Methods: The cross-sectional web-based study was performed in November 2020 using Google Forms. The conventional sample of 3230 university students from Poland (n = 1581) and Ukraine (n = 1649), aged 18–59 (M = 21.40, SD = 3.46), with 59% women, participated in the study. We used standardized questionnaires to measure life satisfaction (SWLS), self-reported physical health (GSRH), perceived stress (PSS-10), coronavirus-related PTSD (PCL-S), anxiety (GAD-7), and depression (PHQ-9). We also developed some questions to assess the exposure to the COVID-19 pandemic, positive effects of the pandemic, religiosity, and physical activity (PA). Results: We found a high prevalence of stress, coronavirus-related PTSD, anxiety, and depression and a low level of life satisfaction and physical health. Polish students, women, and those with insufficient PA levels reported worse physical and mental health than Ukrainians, men, and those who exercised sufficiently during the pandemic. Low perceived stress can directly predict life satisfaction, anxiety, and depression. Low stress also leads to better physical health, sufficient PA levels, high religiosity, and more perceived positive effects of the pandemic. Several indirect effects between particular variables and life satisfaction were also found in the path model. Conclusions: The target group for campus prevention programs is Polish university students, women, and people with insufficient PA levels. Intervention and prevention programs should focus on coping strategies and techniques for improving mental and physical health.