Very few studies of the antiviral potential of lignosulfonates have been published. With the aim of oral application, among various groups of natural products, the relative antiviral potency of lignosulfonate and its ability to rapidly inactivate viruses were investigated. Methods: As target cells, MT-4 cells in suspension and attached Vero cells were used for infections with human immunodeficiency virus (HIV) and human herpes simplex type-1 virus (HSV). Mock- or virus-infected cells were incubated for 3–5 days with various concentrations of test samples, and the viable cell number was determined with the MTT method. For the shorter exposure experiments, higher titers of HIV or HSV were exposed to test samples for 10 or 3 min, diluted to a normal multiplicity of infection (MOI), and applied to the cells. Antiviral activity was quantified by using the chemotherapy index. Results: In the long-exposure system, lignosulfonates showed comparable anti-HIV activity with those of AZT, ddC, and sulfated polysaccharides, and it exceeded those of hundreds of tannins and flavonoids. When the exposure time was shortened, the chemotherapeutic index of the lignosulfonates for HIV was increased 27-fold. At a physiological pH, lignosulfonate showed higher anti-HIV activity than commercial alkali-lignin, dealkali-lignin, and humic acid, possibly due to the higher solubility and purity. Conclusions: With their rapid virus-inactivation capabilities, lignosulfonates may be useful for the prevention or treatment of virally induced oral diseases.