Background and Aims: The COVID-19 pandemic has led to radical and unexpected changes in everyday life, and it is plausible that people’s psychophysical health has been affected. This study examined the relationship between COVID-19 related knowledge and mental health in a Croatian sample of participants.MethodsAn online survey was conducted from March 18 until March 23, 2020, and a total of 1244 participant responses were collected (85.5% were women and 58.4% completed secondary education). Measures included eight questions regarding biological features of the virus, symptoms, and prevention, the Hospital Anxiety and Depression Scale, and Optimism-Pessimism Scale. According to the answers given on the questions on COVID-19 related knowledge, participants were divided in two groups: (1) informed and (2) uninformed on each question. They were then compared in the expressed levels of anxiety, depression, pessimism, and optimism. Full vs. partial mediation models with optimism/pessimism as a mediator in the relationship between anxiety/depression and the accuracy of responses for questions about handwashing and ways of transmission were estimated.ResultsParticipants who responded correctly on the question about handwashing had higher levels of anxiety, depression, and pessimism than those participants whose answer was incorrect, while participants who answered correctly on the question about the percentage of patients who develop serious breathing problems had higher levels of depression than those who answered incorrectly. Lower levels of anxiety and pessimism were observed in the participants who answered correctly about ways of transmission. Higher levels of pessimism were found in participants who scored incorrectly on questions about the efficiency of antibiotics, most common symptoms, and the possibility of being infected by asymptomatic carriers. Higher levels of knowledge about handwashing were predicted by higher levels of anxiety and pessimism. Higher levels of knowledge about ways of transmission were predicted by lower levels of anxiety and lower levels of pessimism. The examined relationships between anxiety/depression and knowledge were mediated by pessimism.ConclusionThe findings of this study suggest that knowledge about COVID-19 may be useful to reduce anxiety and depression, but it must be directed to the promotion of health behaviors and to the recognition of fake news.