Background: Apathy is common in nursing home (NH) residents and it overlaps with depression. This study examines the effects of a multidisciplinary depression program on apathy and depressive motivational and mood symptoms. Methods: Secondary analyses of a stepped-wedge cluster-randomized controlled trial were conducted with six measurements. Sixteen dementia NH units and 17 somatic units were enrolled. In the intervention condition, a program containing depression assessment procedures and multidisciplinary treatment (activating strategies, psychotherapy, and medication) was introduced. Usual care was provided in the control condition. Outcomes were assessed using the 10-item Apathy Evaluation Scale and the Cornell Scale for Depression in Dementia. Results: Intention-to-treat analyses showed that the whole depression management program reduced apathy in dementia units (p < 0.001; Cohen's d, −0.35), and depressive motivational symptoms in somatic units (p = 0.008; Cohen's d, −0.40). Depressive mood symptoms were not affected in both unit types. The effect on apathy in dementia units was mainly attributed to activating strategies (p < 0.001; Cohen's d, −0.73). The effect on motivational symptoms in somatic units was mainly attributed to psychotherapy (p = 0.002; Cohen's d, −0.80). Apathy worsening was associated with pharmacological depression treatment in both unit types (p = 0.009; Cohen's d, 0.35). Conclusions: Depression management may affect apathy and depressive symptoms differently, which underpins the position of apathy as a distinct syndrome. NH professionals can effectively use activating strategies in dementia units, and psychotherapy in somatic units. More research is needed on treating depressive mood symptoms, and on effects of antidepressants in NHs.