London, Ontario is a mid-sized Canadian city which appears to be experiencing a syndemic predominately amongst its marginalized populations. Since 2014, rates of HIV, hepatitis A (HAV), hepatitis C (HCV), and invasive group A streptococcal disease have climbed well above provincial rates amid increasing use of injection drugs. Rates of infective endocarditis have also been on the rise. Extensive public health and community-based efforts were taken in response to these concurrent outbreaks. These efforts included establishing improved client care pathways, creating specialized teams to engage underhoused clients, providing mass immunization, and developing new health promotion campaigns. Rates of HIV and HAV were subsequently controlled locally while rates of HCV, iGAS and infective endocarditis remain high within the community and throughout the province.