Luminal B HER2-negative breast cancer (BC) is the most common type in Indonesian BC patients, and frequently manifests with locally advanced staging. Recurrence often occurs within two years of the endocrine therapy course (primary endocrine therapy (ET) resistance). p53 mutation often exists in luminal B HER2-negative BC, but its application as an ET resistance predictor in those populations is still limited. The primary purpose of this research is to evaluate p53 expression and its association with primary ET resistance in luminal B HER2-negative BC. This cross-sectional study compiled 67 luminal B HER2-negative patients’ clinical data during their pre-treatment period until they completed a two-year course of endocrine therapy. They were divided into two groups: 29 patients with primary ET resistance and 38 without primary ET resistance. Pre-treatment paraffin blocks from each patient were retrieved, and the p53 expression difference between the two groups was analyzed. Positive p53 expression was significantly higher in patients with primary ET resistance [odds ratio (OR) of 11.78 (95% CI: 3.72–37.37,p-value < 0.0001)]. We conclude that p53 expression could be a beneficial marker for primary ET resistance in locally advanced luminal B HER2-negative BC.