Abstract Background Preclinical models suggest synergy between anti-angiogenesis therapy, mammalian target of rapamycin (mTOR), and histone deacetylase inhibitors to promote anticancer activity. Methods This phase I study enrolled 47 patients between April 2012 and 2018 and determined safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) when combining bevacizumab, temsirolimus, and valproic acid in patients with advanced cancer. Results Median age of enrolled patients was 56 years. Patients were heavily pretreated with a median of 4 lines of prior therapy. Forty-five patients (95.7%) experienced one or more treatment-related adverse events (TRAEs). Grade 3 TRAEs were lymphopenia (14.9%), thrombocytopenia (8.5%), and mucositis (6.4%). Grade 4 TRAEs included lymphopenia (2.1%) and CNS cerebrovascular ischemia (2.1%). Six patients developed DLTs across 10 dose levels with grade 3 infection, rash, mucositis, bowel perforation, elevated lipase, and grade 4 cerebrovascular ischemia. The MTD was dose level 9 (bevacizumab 5 mg/kg days 1 and 15 intravenously (IV) plus temsirolimus 25 mg days 1, 8, 15, and 22 IV and valproic acid 5 mg/kg on days 1-7 and 15-21 per orally (PO)). Objective response rate (ORR) was 7.9% with confirmed partial response (PRs) in 3 patients (one each in parotid gland, ovarian, and vaginal cancers). Stable disease (SD) ≥+6 months was seen in 5 patients (13.1%). Clinical benefit state (CBR: PR + SD ≥+6 months) was 21%. Conclusion Combination therapy with bevacizumab, temsirolimus, and valproic acid was feasible, but there were numerous toxicities, which will require careful management for future clinical development (ClinicalTrials.gov Identifier: NCT01552434).