To investigate dietary habits, sleep and psychological well-being of adolescents and medical students during COVID-19 lockdown in Split, Croatia. Methods: We surveyed 1326 students during 2018 and 2019, and compared their responses with 531 students enrolled in May 2020. Perceived stress, quality of life (QoL), happiness, anxiety, and optimism were assessed as proxies of psychological well-being, using general linear modelling. Results: We found no substantial differences in dietary pattern between pre-lockdown and lockdown periods, including the overall Mediterranean diet (MD) adherence. However, the MD pattern changed, showing increased adherence to the MD pyramid for fruit, legumes, fish, and sweets, while cereals, nuts, and dairy intake decreased during COVID-19 lockdown. A third of students reported weight loss during lockdown, 19% reported weight gain, while physical activity remained rather stable. The most prominent change was feeling refreshed after a night’s sleep, reported by 31.5% of students during lockdown vs. 8.5% before; median length of sleep duration increased by 1.5 h. Lockdown significantly affected QoL, happiness, optimism (all p < 0.001), and perceived stress in students (p = 0.005). MD adherence was positively correlated with QoL and study time, and negatively with TV and mobile phone use in pre-lockdown period (all p < 0.001). Interestingly, higher MD adherence was correlated with less perceived hardship and greater happiness and QoL during lockdown. Conclusion: These insights provide valuable information for tailored interventions aimed at maintaining healthy lifestyle in young population. Given the numerous beneficial effects associated with MD adherence, modification of lifestyle through application of lifestyle medicine deserves a priority approach.