Decreased health-related quality of life (HRQoL) is common in patients with cancer. We investigated the effects of dietary intervention and baseline nutritional status on worsening of HRQoL in older patients during chemotherapy. In this randomized control trial assessing the effect on mortality of dietary advice to increase dietary intake during chemotherapy, this post hoc analysis included 155 patients with cancer at risk of malnutrition. The effects of dietary intervention, baseline Mini Nutritional Assessment item scores, weight loss, and protein and energy intake before treatment on the worsening of HRQoL (physical functioning, fatigue) and secondary outcomes (Timed Up and Go test, one-leg stance time, depressive symptoms, basic (ADL), or instrumental (IADL) activities of daily living) were analyzed by multinomial regressions. Dietary intervention increased total energy and protein intake but had no effect on any examined outcomes. Worsening of fatigue and ADL was predicted by very low protein intake (< 0.8 g kg⁻¹ day⁻¹) before chemotherapy (OR 3.02, 95% CI 1.22–7.46, p = 0.018 and OR 5.21, 95% CI 1.18–22.73, p = 0.029 respectively). Increase in depressive symptomatology was predicted by 5.0–9.9% weight loss before chemotherapy (OR 2.68, 95% CI 1.10–6.80, p = 0.038). Nutritional intervention to prevent HRQoL decline during chemotherapy should focus on patients with very low protein intake along with those with weight loss.