A series of new substituted 6-methoxybenzothiazoles was synthesized and evaluated for their anthelmintic activity. The synthesis of the desired compounds was achieved through the key intermediate 2-(2-aminobenzothiazol-6-yloxy)acetohydrazide6. Target compounds were designed to comprise diverse substitutions at the 6-position of the benzothiazole ring varying between the flexibility of a long aliphatic chain and the rigidity of some substituted heterocyclic rings. The in vitro paramphistomicidal activity of 15 of the synthesized compounds was assessed. N-[6-((4-Acetyl-5-(4-chlorophenyl) and (4-nitrophenyl)-4,5-dihydro-[1,3,4]-oxadiazol-2-yl(methoxy)benzothiazol-2-yl]acetamides (32, 33) were considerably active against rumen flukes. The impact of structural substitution on activity was examined. A computational study of the impact of the polar nature and hydrophilic–lipophilic properties was undertaken. An expanded structure–activity relationship (SAR) assessment of the different novel series is also discussed.