This study was performed to investigate the residual characteristics, safety assessment, and pre-harvest interval (PHI) of spiromesifen and chromafenozide in lettuce (Latuca sativa L.) and perilla (Perilla frutescens (L.) Britton) leaves. Samples were harvested periodically, extracted using QuEChERS method, and analyzed by LC-MS/MS. Average recoveries of spiromesifen and its metabolite BSN2060-enol and chromafenozide were ranged from 80.6 to 107.9%, with relative standard deviation < 10%. Spiromesifen and cromafenozide initial residues in lettuce were dissipated to 81.45 and 95.52% after 7 days, with half-lives of 2.89 and 1.69 days respectively. Values in perilla leaves were 76.68 and 61.27% after the same period, with half-lives of 4.25 and 6.30 days, respectively. Risk assessment results showed that %ADI (acceptable daily intake) of spiromesifen and chromafenozide was 6.83 and 0.56, in lettuce and 4.60 and 0.25% in perilla leaves, respectively. Theoretical maximum daily intakes of spiromesifen and chromafenozide were 67.49 and 3.43%, respectively, indicating that residues of both compounds pose no considerable health risks to consumers. This study provides data for setting maximum residue limits and PHIs for the safe use of spiromesifen and chromafenozide in lettuce and perilla.