Homicide committed by a person who subsequently commits suicide within one week of the homicide is a relatively rare event. The current study used an explanatory sequential design, including psychological autopsies, to identify psychiatric and other contributing factors in 35 homicide-suicide cases in northern Gauteng Province, South Africa. This research highlighted the complex multifactorial nature of these events. Identification of high-risk individuals and delineation of contributing factors is important. Early recognition and effective treatment of psychiatric illness, particularly depression and substance use problems, in people experiencing relationship issues (with pending/recent separations) and financial stressors, is an essential component in the prevention of homicide-suicide incidents. Evaluations should always include direct questioning about suicidal and homicidal ideations. Mental health practitioners have a definite role to play in offering comfort, support, and treatment to all those who remain behind after these devastating events. Urgent attention needs to be given to the availability of support and treatment for investigating police officers and surviving family and friends.