Introduction: Smoked fish, particularly catfish and mackerel, plays a vital role in the Ghanaian diet, serving as a rich source of protein and essential nutrients. Smoking is a traditional preservation method widely used to extend the shelf life of fish, enhance flavor, and make it more palatable. However, despite the advantages of smoking, the process does not entirely eliminate the risk of microbial contamination, which can have significant health implications. Aim of Study: This study examined the microbial flora contamination of the smoked fish sold in Ghanaian markets. Methodology: The research was conducted in three markets: Kejetia Market, Ejura Market and Ejusu. A total of 75 different smoke-dried fish including Cat fish (Clarias gariepinus) and Mackerel (Scomber scombrus) from the markets. The fish samples were collected and kept in sterile polythene bags and transported to the laboratory for microbial analysis. Result: The study revealed that out of 75 samples analyzed, approximately 23% (n=17) were found to be contaminated with microorganisms. Escherichia coli had the highest occurrence, detected in 35.2% (6/17) of the total samples. Additionally, Shigella flexneri and Salmonella arizonae were each found in 17.6% (3/17) of the total samples. Klebsiella oxytoca was 11.7% (2/17), and Enterobacter aerogenes, Streptobacillus monilliforms, and Fusobacterium necrophorus each constituted 5.8% (1/17) of the total samples. All the identified isolates were susceptible to gentamycin (100%), and all the isolates were resistant to lincomycin (100%). Overall resistance rates for each antibiotic for all the organisms identified are lincomycin (100%), penicillin (67%), ampicillin (81%), erythromycin (65%), tetracycline (63%), neomycin (61%), cloxaxillin (43%), kanamycin (24%), and sulphamethaxole (13%). All the isolates have 100% resistance to at least three antibiotics used except for Salmonella arizonae. Conclusion: To Address these findings, a collaborative effort is required among regulatory authorities, food producers, and healthcare providers to implement stringent food safety protocols and mitigate the risks associated with contaminated fish consumption.