The application of livestock manure is the leading cause of antibiotic and heavy metal pollution in agricultural soil. However, the effects of oxytetracycline (OTC) and lead (Pb) pollution in the single or combined form on antibiotic resistance genes (ARGs) in the soil need to be further studied. This study was planned to investigate the effects of OTC and Pb application on ARGs, mobile genetic elements (MGEs), and bacterial abundance in the soil. The relative abundance of ARGs and MGEs increased by 0.31-fold and 0.03-fold after the addition of 80 mg kg−1 Pb to the soil, and by 0.49-fold and 0.03-fold after the addition of 160 mg kg−1 Pb. In addition, under the premise of the existence of OTC, the inhibitory effect of a low concentration of Pb on ARG is stronger than that of a high concentration of Pb, resulting in a lower abundance of ARGs. The abundance of ARGs and MGEs increased by 0.11-fold and 0.17-fold after the addition of OTC (30 mg kg−1) to the soil at a Pb concentration of 80 mg kg−1 and by 0.18-fold and 0.04-fold at a Pb concentration of 160 mg kg−1. The addition of OTC and Pb in the soil also decreased the many bacterial communities such as Bacteroidetes, Proteobacteria, Acidobacteria, and Firmicutes. Redundancy analysis (RDA) showed that organic matter content and pH were positively correlated with the abundance of ARGs and MGEs. At the same time, electrical conductivity (EC) had a negative correlation with the abundance of ARGs and MGEs in the soil. Intl1 was significantly associated with tetB, sul1, tetQ, sul2, and sul3. Network analysis illustrated that Actinobacteria, Bacteroidetes, and Proteobacteria were the main host bacteria causing changes in the abundance of ARGs and MGEs, and they were also predominant phylum in the culture environment. This conclusion can provide a reference for the related research of ARGs in soil.