The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak resulted in hundreds of millions of coronavirus cases, as well as millions of deaths worldwide. Coronavirus Disease 2019 (COVID-19), the disease resulting from exposure to this pathogen, is characterized, among other features, by a pulmonary pathology, which can progress to “cytokine storm”, acute respiratory distress syndrome (ARDS), respiratory failure and death. Vaccines are the unsurpassed strategy for prevention and protection against the SARS-CoV-2 infection. However, there is still an extremely high number of severely ill people from at-risk populations. This may be attributed to waning immune response, variant-induced breakthrough infections, unvaccinated population, etc. It is therefore of high importance to utilize pharmacological-based treatments, despite the progression of the global vaccination campaign. Until the approval of Paxlovid, an efficient and highly selective anti-SARS-CoV-2 drug, and the broad-spectrum antiviral agent Lagevrio, many pharmacological-based countermeasures were, and still are, being evaluated in clinical trials. Some of these are host-directed therapies (HDTs), which modulate the endogenic response against the virus, and therefore may confer efficient protection against a wide array of pathogens. These could potentially include Biological Warfare Agents (BWAs), exposure to which may lead to mass casualties due to disease severity and a possible lack of efficient treatment. In this review, we assessed the recent literature on drugs under advanced clinical evaluation for COVID-19 with broad spectrum activity, including antiviral agents and HDTs, which may be relevant for future coping with BWAs, as well as with other agents, in particular respiratory infections.