A series of novel substituted 2-pyrimidylbenzothiazoles incorporating either sulfonamide moieties or the amino group at C2 of the pyrimidine ring were synthesized and evaluated for its antiviral potency. The novel synthesis of the ring system was carried out by reacting guanidine or N-arylsulfonated guanidine with different derivatives of ylidene benzothiazole based on Michael addition pathways. The antiviral activity of the newly synthesized compounds was examined by a plaque reduction assay against HSV-1, CBV4, HAV HM 175, HCVcc genotype 4 viruses, and HAdV7. In the case of HSV-1, it was determined that 5 out of the 21 synthesized compounds exhibited superior viral reduction in the range of 70–90% with significant IC₅₀, CC₅₀, and SI values as compared with acyclovir. In the case of CBV4, nine compounds have shown more than 50% reduction. Comparable results were obtained for seven of these synthesized compounds when evaluated against HAV with only a couple of them showing 50% reduction or more against HCVcc genotype 4. Remarkably, one compound, 9a, has shown broad action against all five examined viruses, rendering it as potentially an effective antiviral agent. The five potent compounds 9a, 9b, 14b, 14g, and 14h against HSV-1 have also presented inhibitory activity against the Hsp90α protein with IC₅₀ in the range of 4.87–10.47 μg/mL. Interestingly, a combination of the potent synthesized compounds with acyclovir led to IC₅₀ values lower than that of acyclovir alone. The potent compounds 9a, 9b, 14b, 14g, and 14h were also docked inside the active site of Hsp90α to assess the interaction pattern between the tested compounds and the active site of the protein.