This study investigated disease outbreaks in farmed Oreochromis niloticus (Nile tilapia) in Siavonga among small-scale cage culture farms on Lake Kariba in order to establish bacterial etiological agents associated with fish mortality and to determine their antibiotic susceptibility. A total of 300 fish samples from 11 farms were aseptically collected and bacteria were isolated from the kidney, liver, brain, and spleen. The isolates were identified using their morphological characteristics and conventional biochemical tests. The antibiotic susceptibility of selected bacteria was determined by the Kirby–Bauer disc diffusion method. The following well-known fish pathogens were identified at a prevalence of Aeromonas spp. (13%), Pseudomonas spp. (10.3%), Micrococcus spp. (9.7%), Klebsiella spp. (8.7%), Lactococcus spp. (7.3%), Streptococcus spp. (7.0%), and Acinetobacter spp. (7.0%). All the isolates tested were susceptible to doxycycline, and complete resistance to ciprofloxacin, co- trimoxazole, and cephalothin was recorded in the Bacillus spp. The observed resistance could be attributed to bacteria from terrestrial sources as fish farmers do not administer antibiotics to fish. To our knowledge, this is the first study to establish the occurrence of several bacterial species infecting tilapia in Zambia and the first to determine the antibiotic susceptibility of fish bacteria among small- scale farms on Lake Kariba. The current study provides baseline information for future reference and fish disease management on Lake Kariba and in Zambia.