Aims: This study examined the microbial flora contamination of the Ghanaian paper currency notes and its antibiotic-resistance in Ejura Municipal, Ashanti Region, Ghana. Study Design: This is a descriptive cross-sectional study designed to assess the profile of microflora contamination of the Ghanaian paper currency notes and its antibiotic-resistance in the Ejura Municipality. Place and Duration of Study: The research was conducted in Ejura, a town in the Ejura Sekyeredumase Municipal District of the Ashanti region of Ghana, from January to May 2019 Methodology: A total of 70 GH¢ notes, 15 each of GH ¢1, GH ¢2, and GH ¢5, 10 each of GH ¢10 and GH ¢20, and 5 of GH ¢50, were randomly sampled from people in various shops, canteens, and commercial drivers. The surfaces of each GH¢ note were gently swabbed, and tenfold serial dilution was inoculated on plate count agar (PCA), MacConkey agar, mannitol salt agar, and deoxycholate citrate agar. PCA, MCA, DCA, and MSA were the media used for the total viable count, Gram-negative rods, Gram-negative enteric bacilli, and Staphylococcus isolation in that order. For bacterial identification, the study used appropriate laboratory and biochemical tests. The data was analyzed using SPSS-IBM version 20.0. Results: It was found that 95.2 % of the 70 GH¢ notes tested positive for one or more bacterial isolates. On each GH¢ note, mean counts on PCA ranged from 3.0 cfu/ml ×105 to 4.8 cfu/ml ×105. Of 124 bacteria isolated. 36 (29.03 %), 32 (25.81%), 16 (12.90 %), 20 (16.13%), 13 (10.48 %), and 7 (5.66 %) were from GH¢1, GH¢2, GH¢10, GH¢5, GH¢20, and GH¢50, respectively. Bacterial isolates were Escherichia coli (25.81%), Staphylococcus aureus (18.55%), coagulase-negative Staphylococcus (15.32%), Klebsiella species (12.10%), Salmonella species (9.68%), Shigella species (8.06%), Pseudomonas aeruginosa (7.26%), and Proteus species (3.23%). Meat shops, commercial drivers, canteens, grocery stores, and vegetable shops contributed 25.81 %, 20.16 %, 19.35 %, 17.74 %, and 16.94 % of GH¢ notes respectively. There was 100% resistance of the isolates to Erythromycin (ERY), and Cotrimoxazole (COT). Amikacin (AMK) was the most effective among the antibiotics as 75% of the isolates were susceptible to it. Conclusion: This study has demonstrated that the GH¢ notes are heavily contaminated with potentially pathogenic bacteria that are highly resistant to the most widely used antibiotics and are a threat to public health.