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<i>Background</i>: The COVID-19 pandemic poses a challenge to global mental health. Loneliness and isolation may put people at higher risk for increased psychological distress. However, there is a lack of research investigating the development of COVID-19-related distress over time. <i>Materials and Methods</i>: We undertook an online survey among general population (N = 1903) in Germany throughout 6 months from the peak transmission period in April to the off-peak period by September 2020. <i>Results</i>: We found that the average prevalence of psychological distress caused by the COVID-19 pandemic significantly rose from 24% to 66% between the peak and off-peak transmission period, respectively. Unemployment rate and loneliness increased negative mental health outcomes, although the number of active COVID-19 cases decreased from April to September. Psychological distress scores increased mostly in female, young, and lonely people. <i>Conclusions</i>: Our results underline the importance of considering innovative alternatives to facilitate employment opportunities, distant contacts, and self-help over the course of the pandemic. Our study highlights the urgent need to pay attention to mental health services specifically targeting female, young, unemployed, and lonely people.