With the rapid growth of aquaculture globally, large amounts of antibiotics have been used to treat aquatic disease, which may accelerate induction and spread of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in aquaculture environments. Herein, metagenomic and 16S rRNA analyses were used to analyze the potentials and co-occurrence patterns of pathogenome (culturable and unculturable pathogens), antibiotic resistome (ARGs), and mobilome (mobile genetic elements (MGEs)) from mariculture waters near 5000 km coast of South China. Total 207 species of pathogens were identified, with only 10 culturable species. Furthermore, more pathogen species were detected in mariculture waters than those in coastal waters, and mariculture waters were prone to become reservoirs of unculturable pathogens. In addition, 913 subtypes of 21 ARG types were also identified, with multidrug resistance genes as the majority. MGEs including plasmids, integrons, transposons, and insertion sequences were abundantly present in mariculture waters. The co-occurrence network pattern between pathogenome, antibiotic resistome, and mobilome suggested that most of pathogens may be potential multidrug resistant hosts, possibly due to high frequency of horizontal gene transfer. These findings increase our understanding of mariculture waters as reservoirs of antibiotic resistome and mobilome, and as yet another hotbed for creation and transfer of new antibiotic-resistant pathogenome.