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Background: Growing evidence suggests that population mental health outcomes have worsened since the pandemic started. The extent that these changes have altered common age-related trends in psychological distress, where distress typically rises until midlife and then falls after midlife in both sexes, is unknown. We aimed to analyse whether long-term pre-pandemic psychological distress trajectories were disrupted during the pandemic, and whether these changes have been different across cohorts and by sex. Methods and findings: We used data from three nationally representative birth cohorts comprising all people born in Great Britain in a single week of 1946 (National Survey of Health and Development, NSHD), 1958 (National Child Development Study, NCDS), or 1970 (British Cohort Study, BCS70). The follow-up data used spanned 39 years in NSHD (1982 to 2021), 40 years in NCDS (1981 to 2001), and 25 years in BCS70 (1996 to 2021). We used psychological distress factor scores, as measured by validated self-reported questionnaires (NSHD: Present State Examination, Psychiatric Symptoms Frequency, and 28- and 12-item versions of General Health Questionnaire; NCDS and BCS70: Malaise Inventory; all: 2-item versions of Generalized Anxiety Disorder scale and Patient Health Questionnaire). We used a multilevel growth curve modelling approach to model the trajectories of distress across cohorts and sexes and obtained estimates of the differences between the distress levels observed during the pandemic and those observed at the most recent pre-pandemic assessment and at the peak in the cohort-specific pre-pandemic distress trajectory, located at midlife. We further analysed whether pre-existing cohort and sex inequalities had changed with the pandemic onset using a difference-in-differences (DiD) approach. The analytic sample included 16,389 participants. By September/October 2020, distress levels had reached or exceeded the levels of the peak in the pre-pandemic life-course trajectories, with larger increases in younger cohorts (standardised mean differences [SMD] and 95% confidence intervals of SMDNSHD,pre-peak = −0.02 [−0.07, 0.04], SMDNCDS,pre-peak = 0.05 [0.02, 0.07], and SMDBCS70,pre-peak = 0.09 [0.07, 0.12] for the 1946, 1958, and 1970 birth cohorts, respectively). Increases in distress were larger among women than men, widening pre-existing sex inequalities (DiD and 95% confidence intervals of DiDNSHD,sex,pre-peak = 0.17 [0.06, 0.28], DiDNCDS,sex,pre-peak = 0.11 [0.07, 0.16], and DiDBCS70,sex,pre-peak = 0.11 [0.05, 0.16] when comparing sex inequalities in the pre-pandemic peak in midlife to those observed by September/October 2020). As expected in cohort designs, our study suffered from high proportions of attrition with respect to the original samples. Although we used non-response weights to restore sample representativeness to the target populations (those born in the United Kingdom in 1946, 1958, and 1970, alive and residing in the UK), results may not be generalisable to other sections within the UK population (e.g., migrants and ethnic minority groups) and countries different than the UK. Conclusions: Pre-existing long-term psychological distress trajectories of adults born between 1946 and 1970 were disrupted during the COVID-19 pandemic, particularly among women, who reached the highest levels ever recorded in up to 40 years of follow-up data. This may impact future trends of morbidity, disability, and mortality due to common mental health problems. 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. [ABSTRACT FROM AUTHOR]