Abstract: With the widespread use of agricultural plastic mulching and veterinary antibiotics, the ecological impacts of their combined contamination in soil environments have received increasing attention. However, most existing studies on the combined effects of polyethylene (PE) microplastics and antibiotics have primarily focused on hydroponic systems or plant-level responses, with limited investigation into soil processes. This study examined the effects of two commonly used veterinary antibiotics-oxytetracycline (OTC) and sulfamethazine (SM2)-at concentrations of 0, 1, and 10 mg·kg^-1 on soil nutrients and enzyme activities under combined contamination with PE microplastics at 0, 0.2%, 1%, 2%, and 5%. A 28-day soil incubation experiment was conducted using agricultural soil collected from Shenyang, China. The effects of PE+OTC and PE+SM2 composite contamination were comparatively analyzed. The results demonstrate that combined PE and antibiotic contamination significantly reduced soil organic matter (SOM), available phosphorus, available potassium, and soil enzyme activities, while significantly increased ammonium nitrogen content. Alterations in soil nutrients and properties were closely associated with changes in enzyme activity. Specifically, compared with the control, PE+OTC and PE+SM2 treatments significantly inhibited alkaline phosphatase (ALP) activity by 34.1% and 40.2%, sucrase (SC) activity by 56.6% and 42.8%, and catalase (CAT) activity by 54.1% and 64.7%, respectively. Comprehensive analysis indicate that PE+OTC exerted a stronger influence on ammonium nitrogen, available phosphorus, and SC activity, whereas PE+SM2 showed greater effects on available potassium, ALP, and CAT activities. Both PE microplastics and antibiotics negatively affected soil fertility, and their combined contamination intensified the effects of individual pollutants. This enhancement may be attributed to hydrogen bonding interactions, mutual adsorption, and altered migration behavior between PE and antibiotics in soil. Currently, most research on PE-antibiotic interactions remains at the laboratory scale. Further studies are needed to elucidate the underlying mechanisms and long-term ecological consequences of composite contamination by PE, OTC, and SM2 in agricultural soils.