Biophysical drying (BPD) is one of the best alternatives for reducing the moisture content from sewage sludge by utilizing biological heat from aerobic reactions. However, the fate of emerging pollutants during BPD process is largely unknown. In this study, the fates of antibiotic resistance genes (ARGs) and metal resistance genes (MRGs) were investigated during a pilot-scale BPD treatment of sewage sludge. A total of 20 types (388 subtypes) of ARGs and 16 types (364 subtypes) of MRGs were detected by metagenomic sequencing and annotation. The total abundance of ARGs decreased from 1.78 ± 0.13 copies/16S rRNA to 0.55 ± 0.01 copies/16S rRNA while the total abundance of MRGs increased from 3.81 ± 0.01 copies/16S rRNA to 6.30 ± 0.02 copies/16S rRNA, showing the distinct behaviors of ARGs and MRGs during BPD process. The ARGs were effectively reduced during the mesophilic and thermophilic stages of BPD process and the reduction of ARGs fitted the first-order kinetic model (p < 0.01). Microbial community analysis showed that the abundance of potential pathogens also decreased during BPD process. On the contrary, the abundances of most MRG subtypes (78.3%) were enriched during BPD process with up to 122-fold change, implying the potential threats for the end product of BPD process. These results together indicate that although the ARGs and potential pathogens can be effectively reduced during BPD process, the safety for the end product still needs to be considered due to the enrichment of MRGs.