Author summary Why was this study done? The COVID-19 pandemic has negatively impacted the mental health of the population, with disproportionate effects among specific subgroups such as women and younger people. Previous research suggests that, in the UK population, long-term trends of psychological distress are expected to reach their highest point during midlife (around age 30 to 45) and decrease towards older age. Little is known about where the potential impact of the COVID-19 pandemic stands in relation to those long-term trends of psychological distress, and whether this impact has been different across cohorts and sexes. What did the researchers do and find? We used data on 16,389 participants from three British birth cohorts representing people born in Britain in 1946, 1958, and 1970, with data on psychological distress collected between 1982 and 2021 (age 36 to 75), 1981 and 2021 (age 23 to 63), and 1996 and 2021 (age 26 to 51), respectively. We measured the long-term psychological distress trajectories of different cohorts (people born in 1946, 1958, and 1970) and sexes (women and men). We found that psychological distress levels increased during the COVID-19 pandemic, reaching or exceeding the highest levels ever recorded in up to 40 years of data, and that this increase was larger among women. What do these findings mean? This study suggests that, during the COVID-19 pandemic, there has been a new peak in the long-term trajectories of psychological distress in the UK population, one that was largely unexpected considering pre-existing trends, in addition to the peak already observed in midlife. This new peak in the psychological distress trajectories has been substantially larger in women than in men, widening the sex inequalities already existing prior to the pandemic onset. This new peak in distress may increase the trends of morbidity, disability, and mortality due to common mental health problems, with women likely being disproportionately affected. Public policies aimed at the provision of support and monitoring of population mental health, particularly among those most disproportionately affected by the pandemic, are needed to tackle existing and prevent future inequalities.