Pseudomonas aeruginosa is a pathogenic bacterium widely distributed in the environment, with increasing concerns about multidrug-resistant (MDR) strains in riverine systems. In this study, we assessed the antibiotic resistance of 50 P. aeruginosa isolates from surface water samples collected at seven distinct sites along the Buriganga River. Antibiotic sensitivity was tested using the Kirby–Bauer Disk Diffusion method. The results showed widespread antibiotic resistance, with 88% of isolates resistant to cefotaxime and tetracycline, followed by 48% resistance to cefepime and 24% to ciprofloxacin. Conversely, most isolates were susceptible to penicillin, aminoglycosides, carbapenems, and fluoroquinolone-class antibiotics, with sensitivity rates of 100, 98, 92, 94, and 96%, respectively. Thirteen isolates (26%) were classified as MDR, predominantly from point-source pollution sites such as industries, medical waste, and municipal waste discharges. Notably, 4% of isolates exhibited resistance to both imipenem and meropenem, raising concerns about the spread of carbapenem-resistant P. aeruginosa in the river. This study highlights the contamination of river water with antibiotic-resistant P. aeruginosa and its potential transmission through aquatic systems. Proper waste management and treatment are critical to controlling the spread of MDR isolates, which pose risks to both public health and the environment.