During the COVID-19 pandemic, medical students were burdened with high levels of stress, anxiety, and depression. The objective of the present study was to investigate predictors of positive mental health among medical students during the COVID-19 pandemic. We conducted an online survey from September 2021 to March 2022. We applied the snowball recruitment technique involving medical students from the University of Catania, Italy. We administered, anonymously, a questionnaire about demographic characteristics, the Depression Anxiety Stress Scale (DASS-21), the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A), and the short form of the Mental Health Continuum (MHC-SF). Participants showed moderate anxiety, depression, and stress levels, and more than half had positive mental health status overall. This finding was inversely related to age, depression severity, cyclothymic, and depressive temperaments. Our results showed that medical students with depressive and cyclothymic temperaments were more at risk of worsening mental health status during the pandemic. Our findings may allow for further developments about the impact of personological characteristics on students’ mental health to enable more efficient support for the most vulnerable.