Purpose: Evidence suggests an increase of depression and anxiety symptoms during the Covid-19 pandemic but most studies relied on cross-sectional designs and/or small samples, and they often overlooked subgroup effects in the impact of the lockdown. We investigated the effect of the pandemic on depression and anxiety symptoms, and whether it differed by employment situation and alcohol consumption. Methods: This longitudinal study used 23 waves of the Covid-Questionnaire (April 2020—July 2021), within the Lifelines cohort from the Netherlands (n = 76,254). Depression and anxiety symptoms were combined in a “mental health score”. Linear fixed-effects models were fitted to analyse trends in mental health throughout the observation period. The moderating role of pre-existing mental health, employment situation, and alcohol consumption was tested. Results: Depression and anxiety symptoms fluctuated considerably during the observation period, with clear peaks in winter 2021, during the strictest lockdown period. Moreover, temporal patterns differed by employment situation and alcohol consumption patterns, suggesting that various subgroups reacted to the pandemic and the lockdown in different ways. Conclusion: Lockdowns increased depression and anxiety symptoms in the Netherlands. The effect was particularly strong for unemployed individuals, those with risky alcohol consumption patterns and those with pre-existing mental health disorders.