The spatiotemporal distribution, source apportionment and combined pollution of 14 antibiotics in natural waters adjacent to mariculture farms of Laizhou Bay in the Bohai Sea were studied. The contribution proportion and quantity of each potential pollution source to antibiotics in natural water bodies were quantitatively described. The correlations between heavy metals and antibiotics and their underlying mechanisms in natural and aquaculture water environment were analyzed. Fourteen antibiotics were detected in natural water and sediment in the coastal area of Laizhou Bay. The maximum concentrations of sulfamethazine and trimethoprim in water reached tens or even hundreds of μg/L in winter. Trimethoprim was the main antibiotic in natural water bodies in winter and summer, and enrofloxacin was the principal antibiotic in sediments. Enrofloxacin, ciprofloxacin and oxytetracycline were detected in all underground water samples; thus, control of these antibiotics needs to be made a priority to mitigate groundwater contamination. PCA-MLR revealed that the potential sources of antibiotics in natural waters of Laizhou Bay include the mariculture wastewater (18.3%), the domestic sewage (63.3%) and the livestock wastewater (18.4%). Therefore, the antibiotic burden of Laizhou Bay was principally from the domestic sewage. In natural water, the concentration of Cu was positively correlated with antibiotics, which might be related to the common sources, the competitive adsorption in sediments and the easy complexation characteristic of Cu and antibiotics. Positive correlations among antibiotics and heavy metals were observed in mariculture sediments, while negative relationships were observed in natural sediments.