Background: Administration of single-agent docetaxel in a weekly schedule may offer similar efficacy, with a more favorable toxicity profile, compared to a three-weekly schedule in patients with metastatic breast cancer. Methods: The original search of Medline, Embase, and Scopus was performed in September 2018 and references were updated with additional searches up to January 2021. Two reviewers independently screened the identified literature based on a predefined set of criteria. Randomized controlled trials investigating the use of weekly versus three-weekly docetaxel in metastatic breast cancer patients were included. Results: Four randomized controlled trials (N = 459 patients) were included in the final analyses. No significant differences were found in terms of objective response rate (risk ratio (RR) 0.75, 95% confidence interval (CI): 0.54 – 1.05), progression-free survival (hazard ratio (HR) 0.95, 95% CI: 0.71 – 1.26) or overall survival (HR 0.95, 95% CI: 0.70 – 1.29) between weekly and three-weekly docetaxel, respectively. Weekly docetaxel was associated with a significantly lower risk of grade 3/4 neutropenia (RR 0.16, 95% CI: 0.10 – 0.27), febrile neutropenia (RR 0.21, 95% CI: 0.08 – 0.55), and neuropathy (RR 0.29, 95% CI: 0.11 – 0.78). Although the risk of epiphora (≥ grade 3/leading to treatment withdrawal, RR 3.62, 95% CI: 1.07–12.22) and onycholysis (≥ grade 2/leading to treatment withdrawal, RR 3.90, 95% CI: 1.34 – 11.32) was increased. Conclusions: Weekly docetaxel is associated with a lower risk of neutropenia, febrile neutropenia and neuropathy than the three-weekly docetaxel schedule in metastatic breast cancer patients. However, the risk of onycholysis, epiphora, and treatment discontinuation seems increased with weekly administration. No significant differences in efficacy outcomes were found. Weekly docetaxel might be an alternative for patients at risk for developing neutropenia.