Influenza A viruses that cause pandemics, as well as other harmful pathogens (e.g., SARS-CoV-2 variants), are known as the ‘silent bioterrorists’ of the 21st century. Due to high mutability, anti-influenza chemotherapeutic treatment is a vital defense strategy to combat both seasonal and pandemic influenza strains, especially when vaccines fail. Consequently, the development of novel therapies to combat this serious threat is of great concern. Hence, in this study, 3-(2-thienyl) acrylic acid (TA) was converted into amides of anti-influenza drugs (aminoadamantanes and oseltamivir) through TBTU-mediated coupling. The crystal structures of the thienyl-based amide hybrids (TA-Am (1), TA-Rim (2), TA-Os-OEt (3), and TA-OsC (4)) were also investigated using single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). Moreover, the antiviral activities of the hybrids against influenza virus A/Fort Monmouth/1/1947 (H1N1), clinically isolated influenza strain A/Wuhan/359/1995 (H3N2), and oseltamivir-resistant A/Jinnan/15/2009 (H1N1) were evaluated in vitro. Amongst the tested thienyl-based amides, bisamide 8 (Boc-Os-Hda-TA) exhibited the most potent activity against influenza virus A (A/Wuhan/359/1995) with an IC₅₀ value of 18.52 μg/mL and a selectivity index (SI) = 13.0.