Purpose The inflammatory response to surgery can cause organ dysfunction that results in postoperative complications, including delirium. Methylprednisolone is an anti-inflammatory drug and could mitigate stress responses. This purpose of the study is to investigate the effects of a single high-dose methylprednisolone on various biomarkers in older people undergoing surgery for hip fractures. Methods In the primary study, 117 patients were included. The biomarkers investigated in this secondary analysis were interleukin (IL) -6, IL-10, troponin-T (TnT), tumor necrosis factor alpha (TNF-alpha), S100 calcium-binding protein B, and soluble urokinase-type plasminogen activator receptor. Blood samples were collected at four time points: (1) before the study intervention (T-before); (2) at time of surgery (T-surgery); on the (3) 1st and (4) 3rd postoperative day (T-P1 and T-P3,T- respectively). Results Patients in the methylprednisolone group had significantly lower adjusted mean IL-6 at T-surgery and T-P1 than the placebo group [15.60 (1.13 pg/mL) vs 47.86 (1.12 pg/mL), p < 0.000 and 111.01 (31.64 pg/mL) vs 198.57 (24.00 pg/mL), p = 0.005]. Furthermore, adjusted mean TnT levels at T-surgery were lower in the methylprednisolone group [20.61 (1.14 ng/mL) vs 24.28 (1.12 ng/mL), p = 0.024) as well as adjusted mean TNF-alpha levels T-P1 (14.31 (1.08 pg/mL) vs 17.64 (1.04 pg/mL), p = 0.025]. Conclusions In this secondary analysis, methylprednisolone had a significant effect on three biomarkers (IL-6, TnT, and TNF-alpha). The potential beneficial effects of methylprednisolone on inflammatory biomarkers reflecting surgical stress response in patients with hip fractures need to be investigated further. Key summary pointsAim Is there an effect of methylprednisolone compared to placebo on the inflammatory-related biomarkers IL-6 and -10, TnT, TNF-alpha, S100B, and suPAR in older people with hip fractures? Finding Patients in the methylprednisolone group had significantly lower IL-6, TNF- alpha and TnT levels than the placebo group. There were no significant differences in any of the other biomarkers. Message Methylprednisolone might have an attenuating effect on inflammatory biomarkers IL-6, TNF- alpha and TnT.