Abstract Purpose This study aimed to evaluate the efficacy and safety of docetaxel rechallenge in HER2-negative metastatic breast cancer (MBC) patients who discontinued docetaxel for reasons other than disease progression. Patients and methods We retrospectively analyzed HER2-negative MBC patients treated with docetaxel-based therapy (DBT) at our institution from 2010 to 2020. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were assessed. Multivariate Cox regression and propensity score matching analysis (PSMA) were used to minimize bias. Results Among 600 patients, 369 only received docetaxel once (control group), while 231 (38.5%) received docetaxel rechallenge as second or later-line therapy (rechallenge group). In the second-line rechallenge subset (143 patients), ORR was 51.0%, and PFS was 6.7 months. Multivariate analysis showed that a response to initial DBT (stable disease [SD] vs. complete response/partial response [CR/PR]: odds ratio [OR] 2.615, 95% confidence interval [CI] 1.373–4.981; p = 0.03) independently predicted the ORR. Beyond second-line rechallenge, the ORR and PFS were 37.5% and 5.6 months, respectively. After PSMA, the rechallenge group demonstrated significantly improved OS compared to the control group: 50.5 months vs. 46.0 months (Hazard Ratio [HR] 0.632; 95% CI 0.455–0.878; p = 0.006). The toxicities reported were manageable, primarily hematologic, with grade 3–4 events occurring in 19.5% of cases. Conclusion This study suggests that docetaxel rechallenge may be an effective and tolerable later-line treatment option for patients with HER2-negative MBC, particularly those who responded to initial DBT. However, further prospective, randomized controlled research is needed to fully evaluate its impact on disease response in this patient population.