Background: Breast cancer remains one of the most prevalent malignancies among women worldwide, and chemotherapy with paclitaxel (PTX) is a cornerstone of treatment. However, the frequent occurrence of drug resistance significantly limits its clinical efficacy, highlighting the need to identify novel molecular targets involved in chemoresistance. Methods: FK506 Binding Protein 10 (FKBP10) expression was determined in PTX-resistant and non-resistant tissues using quantitative polymerase chain reaction (PCR), immunoblotting, and immunohistochemistry (IHC). PTX-resistant BC cell lines were established, and FKBP10 expression was assessed. The effect of FKBP10 on PTX sensitivity in resistant cell lines was evaluated through Cell Counting Kit-8 (CCK-8) as well as colony formation assays. Autophagy and apoptosis were analyzed using immunoblotting and flow cytometry, while a xenograft model was employed to validate the role of FKBP10 in tumor growth and drug response in vivo. Results: FKBP10 expression was significantly upregulated in PTX-resistant tissues as well as cells. Silencing FKBP10 enhanced cellular sensitivity to PTX, reduced autophagy, and stimulated apoptosis in resistant cells. Mechanistically, FKBP10 was found to regulate the protein kinase B (AKT)/cAMP response element-binding protein (CREB) signaling axis. In vivo, FKBP10 depletion inhibited tumor growth and further increased the sensitivity of tumors to PTX. Conclusions: FKBP10 promoted BC chemosensitivity via inhibiting AKT/CREB-mediated autophagy. Therefore, FKBP10 could serve as a target.