Objectives This study aims to assess the effectiveness of a multidomain intervention program on the change in functional status of hospitalized older adults. Design This single-arm, prospective, non-randomized interventional study investigates the efficacy of a multidomain interventional program including cognitive stimulation activity, simple exercises, frailty education, and nutrition counseling. Setting and Participants At a tertiary hospital in southern Taiwan, 352 eligible patients were sequentially enrolled. Included patients were aged ≥65 years (mean age, 79.6 ± 9.0 years; 62% male), scored 3–7 on the Clinical Frailty Scale (CFS), and were hospitalized in the geriatric acute ward. Intervention Those receiving standard care (physical rehabilitation and nutrition counseling) during January–July 2019 composed the historical control group. Those receiving the multidomain intervention during August–December 2019 composed the intervention group. Measurements The primary outcome was the change in activities of daily life (ADL) and frailty status, as assessed by Katz Index and Clinical Frailty Scale, with using the generalized estimating equation model. The length of hospital stay, medical costs, and re-admission rates were secondary outcomes. Results Participants undergoing intervention (n = 101; 27.9%) showed greater improvements in the ADL and CFS during hospitalization (ADL adjusted estimate, 0.61; 95% CI, 0.11–1.11; p = 0.02; CFS adjusted estimate, −1.11; 95% CI, −1.42–−0.80; p < 0.01), shorter length of hospital stay (adjusted estimate, -5.00; 95% CI, −7.99–−2.47; p < 0.01), lower medical costs (adjusted estimate, 0.58; 95% CI, 0.49–0.69; p < 0.01), and lower 30- and 90-day readmission rates (30-day adjusted OR aOR, 0.12; 95% CI, 0.27–0.50; p < 0.01; 60-day aOR, 0.04; 95% CI, 0.01–0.33; p < 0.01) than did controls. Conclusions Participation in the multidomain intervention program during hospitalization improved the functional status and decreased the hospital stay length, medical costs, and readmission rates of frail older people.