Purpose To our knowledge, only one study has assessed Quality of Life (QOL) as a predictor of return to work (RTW) during breast cancer treatment and one has evaluated multidimensional cancer‐related fatigue (CRF) as a determinant of RTW. However, no study has assessed the impact of changes in these variables on RTW. The objective of this study was to evaluate QOL, multidimensional CRF and changes in these variables as determinants of RTW during breast cancer treatment. Methods We performed a longitudinal study of 68 patients with a mean age of 46.97 years (SD = 6.92), who were employed at the time of diagnosis. Women were assessed at the beginning of adjuvant treatments (T0) and followed up with by telephone at three (T1) and 6 months later (T2), using questionnaires (QLQ‐C30; MFI‐20). Results Global QOL, OR = 1.12 [1.01–1.25], sleep disturbance, OR = 1.04 [1.002–1.08], fatigue (QLQ‐C30), OR = 0.93 [0.88–0.99], nausea‐vomiting, OR = 0.84 [0.73–0.97], reduced motivation, OR = 1.49 [1.05–2.11] and general fatigue, OR = 0.79 [0.63–0.99] at T0 were associated with RTW at T1. At T2 global QOL, OR = 1.09 [1.01–1.17], cognitive functioning, OR = 1.10 [1.03–1.17], general fatigue, OR = 1.82 [1.04–3.17] and mental fatigue, OR = 0.29 [0.11–0.81] were associated with RTW. Furthermore, changes in mental fatigue were associated with RTW at T2, OR = 0.02 [0.001–0.29]. Conclusions Quality of life, fatigue and their changes in them, especially cognitive functioning and mental fatigue, can play an important role in predicting the RTW of women with breast cancer. This confirms the importance of multidisciplinary care for cancer and the emergence of a theoretical psychological model of RTW.