This manuscript detailed an investigation into parasitic and bacterial co-infections that caused significant morbidity and mortality in farmed thin-lipped grey mullet (Liza ramada) and keeled mullet (Liza carinata) populations. Examination revealed heavy infestations of the copepod parasite Caligus clemensi in the buccal cavity, gills, and skin. Morphological identification of C. clemensi was confirmed through genetic analysis using 18S rRNA sequencing and phylogenetic analysis. The postmortem examinations revealed internal signs of disease, including liver enlargement, hemorrhages, and ascites, while histopathology demonstrated severe destruction of gill tissues associated with the parasite infection. Bacterial cultures isolated Vibrio parahaemolyticus as the cause of secondary bacterial infections, which was further characterized phenotypically and identified through recA gene sequencing. Concerningly, high rates of antibiotic resistance were detected among the V. parahaemolyticus isolates. Therapeutic prolonged baths with Virocid® disinfectant followed by probiotic treatment with Sanolife Pro-W® effectively cleared the parasite infections, resolved secondary bacterial infections, and improved fish survival rates. In summary, heavy parasite burdens of C. clemensi coupled with multiple antibiotic-resistant V. parahaemolyticus infections, were identified as the primary causes of mullet mortalities. The integrated therapy effectively managed aquaculture outbreaks, providing an alternative to excessive chemical pesticides or antibiotics by eliminating parasitic infestations and controlling secondary vibriosis.