Background: The COVID-19 pandemic has profoundly affected young adults’ lives globally, including those in Germany. This study investigated mental health and quality of life during the pandemic, with a particular focus on mood. Immune fitness, the body’s capacity to respond to health challenges (such as infections) by activating an appropriate immune response, was assessed as a physical health indicator. Methods: Data were collected from 317 participants, aged 18 to 35, via an online survey conducted between November 2021 and March 2022. Participants included 103 men (32.5%) and 214 women (67.5%), with a mean age of 25.5 years (SD = 4.1). Results: Compared to pre-pandemic levels, significant declines in mood, quality of life, immune fitness, and sleep quality were observed during the lockdown periods of the COVID-19 pandemic (p < 0.0125). The most pronounced effects were observed during the second lockdown, with declines extending into the second no-lockdown period for fatigue, depression, happiness, optimism, and immune fitness (p < 0.0125). Significant sex differences were found for the magnitude of mood effects (anxiety, depression, stress). No significant differences were found according to age or occupational status (student vs. work). Conclusions: The COVID-19 pandemic and associated lockdown periods had a significant negative effect on the mood, immune fitness, and well-being of young adults living in Germany.