A high prevalence of mental disorders following COVID-19 has been described. It is therefore essential to elucidate underlying biological mechanisms linking SARS-CoV-2 infection and mental health. The kynurenine and catecholamine metabolic pathways are modulated by inflammation and can affect systemic levels of serotonin and dopamine. Their activity may hence link physical disorders with mental health. We investigated factors that affect kynurenine and catecholamine pathway activity in SARS-CoV-2 infection and recovery. The cross-sectional SIMMUN (n = 165) and longitudinal INCOV cohort (n = 167, Su et al. 2022) were analyzed. Demographic and clinical characteristic, inflammatory markers, SARS-CoV-2 infection, symptoms of depression and anxiety (HADS), and mental stress (PSS-4) served as explanatory variables. Blood serotonin and markers of kynurenine (kynurenine/tryptophan ratio), and catecholamine pathway activity (dopamine 3-O-sulfate, phenylalanine/tyrosine ratio) were modeled by multi-parameter linear regression. In the SIMMUN cohort, the inflammatory marker neopterin (β = 0.47 95% CI: 0.34–0.61), SARS-CoV-2-positivity (0.42 0.16–0.68), mental stress (0.18 0.055–0.31), and age (0.26 0.12-0.39) were positively associated with the kynurenine/tryptophan ratio. The phenylalanine/tyrosine ratio was lower in SARS-CoV-2-positive than uninfected participants (−0.38 −0.68 to −0.08). In the INCOV cohort, markers of inflammation were associated with lower serotonin (IL6: −0.22 −0.38 to −0.053) and dopamine 3-O-sulfate levels (interferon-gamma: −0.15 −0.26 to −0.036). Serotonin (0.76 0.34–1.2) and dopamine 3-O-sulfate levels (0.63 0.28–0.99) were higher during recovery than in acute SARS-CoV-2 infection. SARS-CoV-2 infection, inflammation, age and mental stress are key independent predictors of kynurenine pathway activity, which may influence serotonin availability. The catecholamine pathway was also affected in SARS-CoV-2 infection. Altered activity of these pathways may contribute to impaired mental health following COVID-19. •Mental health impairment is common following COVID-19.•Kynurenine and catecholamine pathway activity might be the pathophysiological link.•Data from two cohorts were analyzed using multi-parameter linear modeling.•Inflammation, SARS-CoV-2 infection, mental stress, age influence kynurenine/tryptophan.•Inflammation was associated with lower systemic serotonin and dopamine availability.