Background <p>Tramadol misuse poses a significant public health and safety risk globally. However, research on this topic is limited in informal settlements, particularly among youth in sub-Saharan Africa (SSA). We assessed the trends, frequency, and social factors associated with the severity of Tramadol misuse among the youth residing in urban informal settlements in Ghana.</p> Methods <p>Cross-sectional data from 200 individuals who use Tramadol aged 15–35 years from selected communities in the Asokore Mampong Municipality were analyzed. The severity of Tramadol misuse was assessed with the item “Have you ever used Tramadol for any reason other than medical? If yes, how often do you take Tramadol?” with a 5-point response scale. Multivariable ordinal logistic regression models evaluated the associations between sociodemographic factors and the severity of Tramadol misuse.</p> Results <p>Tramadol was used daily (44.5%), multiple times (68.5%), and in combination with other substances, mainly energy drinks (60%) or alcohol (12.5%). Our regression models showed that being younger (aOR = 0.87; 95%CI = 0.42–0.98); male (aOR = 1.87; 95%CI = 1.16–2.29); unemployed individuals (OR = 1.02; 95%CI = 1.50–2.86), and having low income (GH¢300–699[US$19.3–45]: aOR = 2.16; 95%CI = 1.01–4.65); &lt; GH¢300[US$ 19.3]: aOR = 2.59; 95%CI = 1.13–5.95) were associated with higher odds for severity of Tramadol misuse. Having higher education (high school: aOR = 0.64; 95%CI = 0.25–0.96); tertiary (aOR = 0.58; 95%CI = 0.23–0.89), lowers the odds for the severity of Tramadol misuse.</p> Conclusion <p>Challenged social well-being indicators relate to the severity of Tramadol misuse among youth in urban informal settlements in Ghana. Interventions of regular drug surveillance, drug use educational programs, and the creation of gainful employment may help reduce Tramadol and other substance misuse among youth living in informal settlements.</p>