A method and a system for calculating tumor neoantigen burden (TNB) are provided. The method includes: step S1: processing a normal sample and a tumor sample, sequencing a specific region and detecting somatic mutations in the sample; step S2: annotating and filtering the somatic mutations, and translating to obtain mutant peptide sequences of a patient; step S3: filtering the mutant peptide sequences to obtain neopeptide sequences based on a proteome of the normal sample; step S4, performing a human leukocyte antigen (HLA) typing analysis based on alignment data of the normal sample to obtain HLA genotypes of the sample; step S5, predicting binding affinities between the neopeptide sequences and the HLA genotypes to obtain specific neoantigens of the sample, and performing a weighted scoring on each of the specific neoantigens and calculating the TNB of the sample.