Abstract Purpose This review aims to collect the available documents on the clinical safety of Ac-225 radiopharmaceuticals targeted alpha radionuclide therapy and summarize practical safety data recommended for clinical development of Ac-225 radiopharmaceuticals. Methods A comprehensive literature search was conducted using two bibliographic databases, ClinicalTrials.gov and PubMed/MEDLINE. The search was constructed using the following terms: (A) “Actinium” OR “Ac-225” OR “225Ac” OR “[225Ac]Ac” AND (B) “safety” OR “toxicity” OR “side-effect”. Results This review included 42 studies. Most of the studies looked at prostate cancer (24 studies), while fewer studies (10 studies) explored neuroendocrine tumors. Emerging targets such as FAP (3 studies), DOTA-substance P (2 studies), DOTA-LM3, Rosopatamab Tetraxetan, and Lintuzumab (each 1 study) were also examined. The most frequently reported adverse events -based on CTCAE v5.0 were hematotoxicity, renal toxicity, and xerostomia, followed by fatigue, weight loss, loss of appetite, and nausea. Renal toxicity was less frequent compared to xerostomia (seen in PSMA therapy) and hematologic events, with severe renal toxicity (grade 3/4) reported in a limited number of patients, particularly those with baseline renal impairment. Several studies highlighted no cases of serious acute adverse events or treatment discontinuation due to adverse events. Conclusions In summary, the literature indicates a high safety profile with acceptable toxicity for Ac-225 based TAT. This paper provides, to the best of our knowledge, the most comprehensive clinical information on safety of TAT with different Ac-225 radiopharmaceuticals, in different cancer patients until today. Data in the coming years will certainly strengthen the knowledge of short- and long-term toxicities and would facilitate risk-benefit assessments.