Helicobacter pylori is a pathogen related to severe diseases such as gastric cancer; because of rising antimicrobial-resistant strains, failure to eradicate H. pylori with antibiotics has increased worldwide. Multidrug-resistant H. pylori and gastric cancer is common in Mongolia; therefore, we aimed to explore alternative antimicrobial treatments and the genomes of resistant strains in this country. A total of 361 H. pylori strains isolated from patients in Mongolia were considered. Minimal inhibitory concentrations for two fluoroquinolones (ciprofloxacin and moxifloxacin), rifabutin, and furazolidone were determined via two-fold agar dilution. Genomic mutations in antibiotic-resistant strains were identified by next-generation sequencing using the Illumina Miseq platform and compared with genes from a reference H. pylori strain (26695). The resistance rate of H. pylori strains to quinolones was high (44% to ciprofloxacin and 42% to moxifloxacin), and resistance to rifabutin was low (0.5%); none were resistant to furazolidone. Most quinolone-resistant strains possessed gyrA gene mutations causing amino acid changes (e.g., N87K, A88P, and D91G/Y/N). While one rifabutin-resistant strain had amino acid-substituting mutations in rpoB (D530N and R701C), the other had three novel rpoB mutations; both rifabutin-resistant strains were sensitive to furazolidone. Overall, our findings suggest that rifabutin and/or furazolidone may be an alternative, effective H. pylori treatment in patients who have failed to respond to other treatment regimens.