Despite nearly 5000 United States Food and Drug Administration (FDA)-tracked trials, no new FDA- or European Union-approved Coronavirus Disease 2019 (COVID-19) drug was discovered during the COVID-19 pandemic. Fortunately, drugs developed before the pandemic proved highly effective, particularly when used early in vaccinated patients. The most powerful treatments are antivirals targeting the spike structural protein and two non-structural proteins (NSPs), NSP5 (main protease [Mpro]) and NSP12 (RNA-directed RNA polymerase [RdRp]). Notably, two studies published before the pandemic and one shortly after its declaration had already identified these three key targets. New monoclonal antibodies were designed to block the spike protein from binding to the host cell. However, all such antibodies were eventually rendered ineffective by emerging viral variants. Several drugs previously used for Middle East respiratory syndrome, Ebola, respiratory syncytial virus, and other viruses work by disrupting the replication activity of Mpro and RdRp. Convalescent plasma, a treatment used since 1900, showed mixed results. For hyperinflammation, only three rheumatoid arthritis drugs and one glucocorticoid, also used in arthritis treatment, received approval. No new approaches were developed to treat blood clots or improve oxygenation. Despite a wartime-like focus and unprecedented research intensity, no respiratory illness, including COVID-19, has yet been cured. Using a personal database of 3050 therapeutic research papers, along with data from ClinicalTrials.gov and Google Scholar, this review examines approved, promising, and ineffective COVID-19 therapeutics. Potential candidates currently undergoing clinical trials are identified to highlight future therapeutic possibilities and guide ongoing research efforts.