<p>A range of neuropsychiatric symptoms (including “brain fog”) following COVID-19 are clinically prevalent, yet their biological mechanisms remain unclear. Observational studies indicate that this association may be linked to alterations in brain structure and function post-COVID-19; however, it is uncertain whether this relationship is causal. The study data is derived from the summary statistics of a genome-wide association study (GWAS), where COVID-19 encompasses three phenotypes: critical illness (respiratory support or death; <i>n</i> = 1,086,211), hospitalization (<i>n</i> = 2,095,324), and SARS-CoV-2 infection (<i>n</i> = 2,597,856); Brain imaging-derived phenotypes (IDPs) include cortical structures (<i>n</i> = 51,665), subcortical brain structures (<i>n</i> = 30,717), and brain functional networks (<i>n</i> = 47,276); Neuropsychological symptoms comprise ten phenotypes, including cognitive performance (<i>n</i> = 51,710 to 480,359). We conducted a two-sample Mendelian randomization (MR) analysis to explore potential causal relationships between COVID-19 and IDPs, as well as neuropsychological symptoms. Sensitivity analyses were subsequently performed to evaluate the robustness of the results. We identified causal relationships between COVID-19 and 22 cortical structure phenotypes, one subcortical brain structure phenotype, five brain functional network phenotypes, and one neuropsychological symptom phenotype, with some overlap across different COVID-19 phenotypes. Notably, COVID-19 was predominantly negatively correlated with these phenotypes. Our findings suggest a weak causal relationship between COVID-19 and IDPs, as well as neuropsychological symptoms. Although further research is necessary to validate these relationships, these findings may contribute to a better understanding of the associations between COVID-19, IDPs, and neuropsychological symptoms.</p>