Dietary ingredient and nutrient composition may affect the efficacy of additives in broilers. Specific feed ingredients can represent dietary challenging conditions for broilers, resulting in impaired performances and health, which might be alleviated by dietary probiotics and postbiotics. We assessed the effects of a Lactobacilli probiotic (Pro) and postbiotic (Post) when added to a standard (SD) and challenge (CD) diet. A completely randomized block study with 2 diets (SD, CD) and 3 additive conditions (Control, Pro and Post) involving 1,368 one-day-old Ross male broilers, equally distributed among 36 pens, from d1 to d42 was conducted. Both diets were formulated to contain identical levels of nutrients, with CD formulated to be richer than SD in nonstarch polysaccharides using rye and barley as ingredients. Readout parameters included growth performance parameters, footpad lesions score, blood minerals and biochemical parameters, and tibia health, strength, and composition. Compared to SD, CD decreased BW (1,936 vs. 2,033 g; p = 0.001), increased FCR (p < 0.01) and impaired tibia health and strength (p < 0.05) at d35, thereby confirming the challenging effect of CD. Pro and Post increased BW in CD (+4.7 and +3.2%, respectively, at d35; P < 0.05) but not in the SD group, without affecting FCR. Independently of the diet, Pro increased plasma calcium, phosphorus and uric acid at d21 (+6.2, +7.4, and +15.5%, respectively) and d35 (+6.6, +6.2 and +21.0%, respectively) (P < 0.05) while Post increased plasma magnesium only at d21 (+11.3%; P = 0.037). Blood bile acids were affected by additives in an age- and diet-dependent manner, with some opposite effects between dietary conditions. Diet composition modulated Pro and Post effects on broiler growth performance. Additionally, Pro and Post affected animal metabolism and leg health diet-dependently for some but not all investigated parameters. Our findings show that the effects of pro- and postbiotics on the growth performance and physiology of broilers can be dependent on diet composition and thus possibly other factors affecting diet characteristics.