Heart failure (HF) affects approximately 5.1 million adults in the USA, with expectations of a rise to nearly 8 million adults by 2030. Patients with HF are at increased risk for morbidity/mortality, and comorbidities can further complicate care for these patients. Diabetes mellitus, chronic pain, arrhythmias, and depression are diagnoses that often coexist with HF. Medications commonly used to treat these comorbidities may induce or worsen HF symptoms, so determining appropriate drug therapy is important. Healthcare providers must understand the relationship between these medications and HF in order to improve prescribing practices to increase patient safety and reduce morbidity and mortality. This manuscript discusses the association between certain medications used to treat the aforementioned diagnoses and their relationship to HF. The purpose of this article is to provide guidance on which pharmacologic options require special consideration, increased monitoring, or complete avoidance in HF patients with diabetes mellitus, chronic pain, arrhythmias, and/or depression.