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Simple Summary: One of the most prevalent malignancies across the world is female breast cancer, accounting for 25% of all diagnosed cancers. Physical exercise has been recognized as an important strategy for prevention and treatment during the cancer continuum. Home-based exercise programs can produce greater adherence rates than in-person interventions. However, the majority of home-based programs are carried out employing practical guides, brochures or electronic materials without supervision, which can increase the risk of injury and adverse effects. The aim of this study was to analyze the effect of a synchronous-supervised online home-based exercise program during 24 weeks on body composition, physical fitness and adherence compared to an exercise recommendation group without supervision with patients undergoing breast cancer treatment. We confirmed that supervised home-based exercise interventions can be an interesting strategy to improve physical fitness and adherence rates in breast cancer patients undergoing treatment. The purpose of the present study was to analyze the effect of a synchronous-supervised online home-based exercise program (HBG) during 24 weeks on body composition, physical fitness and adherence compared to an exercise recommendation group (ERG) without supervision with patients undergoing breast cancer treatment. Fifty-nine female breast cancer patients (31 in HBG and 28 in the ERG) undergoing cancer treatments participated in the present randomized clinical trial. The exercise program consisted of a 60 min combined resistance and aerobic supervised exercise session (6–8 points on Borg Scale CR-10, moderate intensity), twice a week during 24 weeks. The exercise recommendation group only received general recommendations to comply with the current ACSM guidelines. Body composition and physical fitness were assessed at baseline, 12 weeks and 24 weeks of the program. Adherence to the intervention was measured according to the minutes of exercise completed per session during each week. A general linear model of two-way repeated measures showed significant improvements (p < 0.05) in physical fitness that were observed in the home-based exercise group at the baseline, 12-week and 24-week assessments compared to the exercise recommendation group. Adherence was also higher in the home-based exercise group. However, no changes (p > 0.05) in body composition between groups and moments were observed. In this sense, supervised home-based exercise interventions can be an interesting strategy to improve physical fitness and adherence rates in breast cancer patients undergoing treatment. [ABSTRACT FROM AUTHOR]