This investigation employed a between-participant design comparing acute and chronic changes in brain-derived neurotrophic factor (BDNF), cathepsin B (CatB), insulin-like growth factor-1 (IGF-1), and interleukin-6 (IL-6) across four resistance training (RT) protocols differing in proximity to failure, while also examining inter-biomarker correlations. Thirty-eight resistance-trained men completed an eight-week intervention, training three times per week, allocated to one of four groups based on repetitions-in-reserve (RIR): 4–6 RIR, 1–3 RIR, 0–3 RIR, and 0 RIR. Serum was collected immediately before and after training on day 1 of weeks 1 and 7. The analysis revealed the main effects of Session for BDNF and IL-6 (posterior probability > 99%), indicating exercise-induced elevation independent of proximity to failure. Additionally, CatB demonstrated a Session × Week interaction (posterior probability > 99%), indicating a difference in the acute response between week 7 and week 1. No compelling evidence emerged for IGF-1 effects, and inter-biomarker correlations were weak and inconsistent. Notably, this is the first investigation to demonstrate RT-induced transient CatB elevation. These findings suggest that exercise-induced neuroprotective biomarker responses may be achieved while training relatively far from failure, potentially avoiding the neuromuscular fatigue, injury risk, and recovery demands associated with failure training.