Substance use continues to be a social problem globally. Around the world, approximately 275 million people use drugs, including 15% of South Africans, with over 36 million succumbing to drug disorders. In the Gauteng Province, about 55% of autopsies of deceased medicolegal cases (2003–2012) showed the presence of one or more illicit drugs in Pretoria. Most research shows that around one-third of people who have problems with alcohol and drugs are homeless. Evidence suggests that homeless people are often denied access to even the most essential assistance, including healthcare. This study assessed the healthcare-seeking behaviors of homeless substance users during the COVID-19 lockdowns in Gauteng, South Africa. A qualitative approach using an exploratory design assessed referrals based on those suffering from symptoms of COVID-19 during the lockdown period between 2020 and 2022. Data were collected from 25 homeless substance users in the City of Tshwane, Gauteng, through unstructured interviews. Three themes based on the study objectives included the types of healthcare services consulted, the determinants of health-seeking behaviors, and challenges experienced while seeking healthcare. Of the twenty-five participants, aged twenty-one to fifty, thirteen suffered from COVID-19 symptoms. Five used formal healthcare systems and eight used informal healthcare systems. Older participants access healthcare services, while less of the younger population use them. Barriers that are encountered while seeking medical services entail marginalization, stigmatization, and a lack of social support. Despite the formidable barriers posed by homelessness and substance use, homeless individuals demonstrated remarkable resilience in their efforts to access healthcare services during the COVID-19 lockdowns. This study highlights the importance and urgent need for harm reduction strategies and policy development for long-term service provision to this population, as well, as the literature on equity, diversity, and inclusion as a foundation for the rights of marginalized populations and groups. Future research directions should focus on harm reduction among this population group of homeless substance users.