The COVID-19 pandemic has contributed to significant societal challenges, including increased substance misuse. The COVID stress syndrome is a constellation of interrelated processes that occur in response to pandemics, including danger/contamination fears, fears concerning economic consequences, xenophobia, compulsive checking/reassurance-seeking, and pandemic-related traumatic stress symptoms. In the present study, using a sample of 812 adults collected during the early stages of the COVID-19 pandemic in May 2020, we examined the relations between identified profiles of the COVID Stress Scales (CSS) and behavioral and cognitive aspects of substance misuse. Using profile analysis via multidimensional scaling (PAMS), we identified two core profiles of the CSS, which explained 60% of the variance in participant responding: 1) High compulsive checking & Low xenophobia and 2) High xenophobia & Low danger/contamination. The first profile is consistent with the COVID stress syndrome, while the second profile aligns with the COVID disregard syndrome, which is a constellation of interrelated processes distinguished by a denial or downplaying of the seriousness of the COVID-19 pandemic and lack of perceived vulnerability to disease. Both profiles demonstrated significant positive correlations with drug and alcohol misuse, respectively. However, only the High xenophobia & Low danger/contamination profile demonstrated relations with cognitive aspects of substance misuse via positive and negative correlations with positive and negative expectancies of alcohol use, respectively. These findings provide further support for the relationship between the COVID stress syndrome and substance misuse and offer insight into how unique profiles of this syndrome may impact pandemic-related mental and public health interventions.