Abstract Purpose ¹⁷⁷Lu-DOTATATE targeting the somatostatin receptor (SSTR) is utilized for treatment of neuroendocrine tumors (NETs). Onalespib, a heat shock protein 90 (HSP90) inhibitor, has demonstrated radiosensitizing properties and may thus enhance the effect of ¹⁷⁷Lu-DOTATATE. Consequently, the aim of this study was to assess the potential of Onalespib in combination with ¹⁷⁷Lu-DOTATATE in vivo and to examine the toxicity profiles of the treatments. Methods ¹⁷⁷Lu-DOTATATE selectivity and distribution in NET xenografts were studied using biodistribution and autoradiography. Therapeutic effects of Onalespib in combination with ¹⁷⁷Lu-DOTATATE were studied in NET xenografts. Histological analyses were used to assess molecular effects from treatment and to establish toxicity profiles. Results Biodistribution and autoradiography confirmed the SSTR-selective tumor uptake of ¹⁷⁷Lu-DOTATATE, which was unaffected by Onalespib treatment. Immunohistochemistry verified molecular responses to Onalespib therapy in the tumors. While Onalespib and ¹⁷⁷Lu-DOTATATE monotherapies resulted in a 10% and 33% delay in tumor doubling time compared with control, the combination treatment resulted in a 73% delayed tumor doubling time. Moreover, combination treatment increased complete remissions threefold from ¹⁷⁷Lu-DOTATATE monotherapy, resulting in 29% complete remissions. In addition, histological analyses demonstrated radiation-induced glomerular injury in the ¹⁷⁷Lu-DOTATATE monotherapy group. The damage was decreased tenfold in the combination group, potentially due to Onalespib-induced HSP70 upregulation in the kidneys. Conclusion Treatment with Onalespib potentiated ¹⁷⁷Lu-DOTATATE therapy of NET xenografts with a favorable toxicity profile. Utilizing Onalespib’s radiosensitizing properties with ¹⁷⁷Lu-DOTATATE may lead to better therapeutic results in the future and may reduce unwanted side effects in dose-limiting organs.