Abstract Crises have the potential to affect mental well-being (MWB), especially at vital stages of personal development such as adolescence. The objective of this study was to investigate the 2016-21 trends of social inequalities in the MWB of adolescents in Barcelona, stratifying by sex. Sequential, cross-sectional study based on the FRESC survey, held by the ASPB, representative of 8th and 10th grade adolescents (13-16 years old) schooled in Barcelona, in 2016 (N = 2,154) and 2021 (N = 2,299). MWB was examined using the validated WEMWBS, scoring from 14 (lowest) to 70 (highest) MWB. A temporal trend analysis of inequalities in MWB was carried out using the student socioeconomic status (SES) (low/average/high), measured with the validated FAS. For each group, the effect size of the WEMWBS means was measured with Cohen’s D. Linear regressions were performed, adjusting for academic grade, student country of origin, type of school and school index of vulnerable students. Adjusted β coefficients (aβ) and their statistical significance (p<.05) were estimated. In 2016, boys had higher MWB mean scores than girls (54.0 vs 50.8) (p<.01). In 2021, sex differences persisted, but with lower scores (51.7 vs 47.0) (p<.01) and still with a moderate effect size (0.52 in 2021 vs 0.40 in 2016). In multivariate regression models, boys in low SES showed the greatest MWB decrease in 2016 (low vs high SES: aβ= -3.44; p<.01). A significant temporal trend 2016-2021 of MWB worsening was observed in all groups, except for boys in low SES. The greatest deterioration in MWB was observed in girls, similarly in different SES (low SES: aβ= -3.52; p<.01). Boys in low SES showed the worst MWB in 2016 whereas all SES categories of girls had a significant trend of deterioration in MWB (2016-21). The latter could be attributed, among other factors, to a differential effect of the COVID-19 pandemic. These results underline the importance of addressing inequalities in the MWB, particularly among adolescent girls. Key messages • This study reveals a deterioration in mental well-being temporal trends (2016-2021) among adolescents in Barcelona, especially in girls. • Findings emphasize the need to address social inequalities for improving mental well-being outcomes in adolescent populations.