Osimertinib is the standard first-line options for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). Co-mutations in TP53 results in poor survival for patients. However, the studies on treatment options and clinical outcomes of patients with EGFR-TP53 co- mutation are limited. Patients with EGFR mutation-positive locally advanced or metastatic NSCLC carrying TP53 mutations were recruited from two institutions and randomly allocated into two groups, either receiving osimertinib plus chemotherapy (Osi + Chemo group) or osimertinib monotherapy (Osi group). The progression-free survival (PFS) was evaluated as the primary endpoint and the response was also assessed. Between January 2020 and August 2023, ninety-eight patients were enrolled with 47 and 51 patients receiving combination therapy and the monotherapy. After a median follow-up of 19.2 months, overall response rate (ORR) was 80.0% vs. 71.7% (p = 0.36), favoring Osi + Chemo group, as well as in disease control rate (DCR) (91.4% vs. 80.4%, p = 0.45). The median PFS in the Osi + Chemo group was 26.0 months versus 20.7 months in the Osi group, but there was no significant difference (p = 0.34). The subgroup analysis indicated that for patients with L858R mutation, Osi + Chemo therapy significantly prolonged the median PFS (not reached [NR] versus 17.1 months, p = 0.03), but showed no benefit in patients with 19Del (20.6 months versus NR, p = 0.31). Osimertinib plus chemotherapy has a tendency to increase ORR and prolong PFS in NSCLC with EGFR and TP53 co-mutations, particularly in patients with L858R mutation.