Background: The TP53 tumor suppressor gene plays an important role in preventing and inhibiting the growth of tumor by regulating cell cycle, apoptosis and DNA repair. Meanwhile, the TP53 gene is one of the most frequently altered gene in non-small cell lung cancer (NSCLC) patients. Mutant TP53 (TP53-MUT) may lose tumor suppressor activity and gain tumor promoting functions, which play an important role in cancer risk, therapy resistance and poor prognosis. The impact of TP53-MUT on the prognosis of NSCLC patients need to be further studied. Methods: We obtained genomic and clinical data from The Cancer Genome Atlas (TCGA). Mutation profiles, the TMB, disease-free survival (DFS), and overall survival (OS) were compared between patients with different TP53-MUT statuses. Results: TP53-MUTs were detected in 46.6% of patients with lung adenocarcinoma (LUAD) (264 of 566) and 82.3% of those with lung squamous cell carcinoma (LUSC) (401 of 487). The most frequently co-mutated genes in patients with LUAD carrying a TP53-MUT included classic driver genes such as epidermal growth factor receptor (EGFR) and anaplastic large-cell lymphoma kinase (ALK), while Kirsten rat sarcoma viral oncogene (KRAS) mutations and TP53-MUTs appear to be mutually exclusive. This mutual exclusivity was not observed in patients with LUSC, in whom titin (TTN) and CUB and Sushi multiple domains 3 (CSMD3) were the most frequently co-mutated genes. A higher TMB was significantly associated with TP53-MUTs in patients with LUAD but not in those with LUSC. In patients with stage I-III NSCLC who had undergone surgery, there was no significant difference in DFS between patients carrying TP53-wildtype (TP53-WT) and TP53-MUTs, irrespective of histology or mutation type. However, the presence of TP53-MUT was associated with shorter OS in patients with LUAD (49 vs. 54 months, respectively; P=0.13) and significantly longer OS in those with LUSC (62 vs. 29 months, respectively; P=0.015). Conclusions: In contrast to most previous studies, we revealed TP53-MUT characteristic in NSCLC patients according to histology-specific differences and the association between TP53-MUT and the mutation landscape, the TMB, and the OS. These findings suggest a need for individualized management for patients with LUAD and LUSC who carry a TP53-MUT, and warrant further research.