The bubble map of Figure 8 summarizes the pleiotropic activity of HCQ evaluated in this review. As highlighted by the colorimetric variation, the research, in the early 2000s, has been focused on the application of HCQ as an antimalarial drug (blue color). In contrast, in the last few years, scientists have moved their attention to the influence of HCQ on many pathways involved in inflammation, infections, autoimmune diseases, cardiovascular pathologies, and diabetes (blue to green color). Finally, in the last months, it is evident that the rapid spread of the COVID-19 pandemic has led to the revaluation of HCQ in viral infections (yellow color). However, the analysis of currently available clinical studies showed that the administration of HCQ to prevent and cure COVID-19 infection is questionable, since results from clinical trials are contrasting, and the last data did not support the use of HCQ for the treatment and prevention of COVID-19 disease. Despite these results, HCQ is considered to be a safe drug since it is generally better tolerated than other 4-aminoquinolines, such as CQ. Hence, nowadays, HCQ arises as a first-line treatment in managing autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and Sjögren syndrome, mainly in association with methotrexate or corticosteroids, showing a synergistic effect on disease control. It also improves glucose and lipid homeostasis and revealed significant antibacterial activity in combination with DXC. To better characterize HCQ activity, computational models should be useful for targeting and docking the molecular features responsible for its mechanism of action. Based on this work, it should be possible to hypothesize future applications of HCQ in medical therapy.