Abstract Background There is evidence that mental health problems are increasing and substance use behaviours are decreasing. This paper aimed to investigate recent trends in mental ill health and health-related behaviours in two cohorts of UK adolescents in 2005 and 2015. Methods Prevalences in mental health (depressive symptoms, self-harm, anti-social behaviours, parent-reported difficulties) and health-related behaviours (substance use, weight, weight perception, sleep, sexual intercourse) were examined at age 14 in two UK birth cohorts; Avon Longitudinal Study of Parents and Children (ALSPAC, N = 5627, born 1991–92) and Millennium Cohort Study (MCS, N = 11 318, born 2000–02). Prevalences and trend estimates are presented unadjusted and using propensity score matching and entropy balancing to account for differences between samples. Results Depressive symptoms (9% to 14.8%) and self-harm (11.8% to 14.4%) were higher in 2015 compared with 2005. Parent-reported emotional difficulties, conduct problems, hyperactivity and peer problems were higher in 2015 compared with 2005 (5.7–8.9% to 9.7–17.7%). Conversely, substance use (tried smoking, 9.2% to 2.9%; tried alcohol, 52.1% to 43.5%, cannabis, 4.6% to 3.9%), sexual activity (2% to 0.9%) and anti-social behaviours (6.2–40.1% to 1.6–27.7%) were less common or no different. Adolescents in 2015 were spending less time sleeping (<8 h 5.7% to 11.5%), had higher body mass index (BMI) (obese, 3.8% to 7.3%) and a greater proportion perceived themselves as overweight (26.5% to 32.9%). The findings should be interpreted bearing in mind limitations in ability to adequately harmonize certain variables and account for differences in attrition rates and generalizability of the two cohorts. Conclusions Given health-related behaviours are often cited as risk factors for poor mental health, our findings suggest relationships between these factors might be more complex and dynamic in nature than currently understood. Substantial increases in mental health difficulties, BMI and poor sleep-related behaviours highlight an increasing public health challenge.