A series of 5‐nitroimidazole‐based 1,3,4‐thiadiazoles were prepared and tested for antibacterial activity against Helicobacter pylori. The anti‐H. pylori activity of target compounds along with the commercially available antimicrobial metronidazole was evaluated by comparing the inhibition‐zone diameters determined by the paper disc diffusion bioassay. From our bioassay results against 20 clinical isolates it is evident that piperazinyl, 4‐methylpiperazinyl, 3‐methylpiperazinyl, and 3,5‐dimethylpiperazinyl analogs (6a, 6b, 6e, and 6f, respectively) and pyrrolidine derivative 7 had strong activity at 0.5 µg/disc (average of inhibition zone >20 mm) while metronidazole had no activity at this dose. Compound 6f containing the 3,5‐dimethylpiperazinyl moiety at the 2‐position of the 5‐(1‐methyl‐5‐nitro‐1H‐imidazol‐2‐yl)‐1,3,4‐thiadiazole skeleton was the most potent compound tested at low concentrations.