Purpose: This study aimed to evaluate the effects of active transcranial direct current stimulation (tDCS) compared with sham stimulation on circulating brain-derived neurotrophic factor (BDNF), pain-related outcomes, working memory, and inflammatory and neuroplasticity biomarkers. Methods: PubMed/MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov were searched from inception to May 2026. Randomized and controlled clinical trials comparing active with sham tDCS in adults were included. The primary outcome was post-treatment BDNF concentration. Secondary outcomes included pain intensity, pain catastrophizing, pain-related disability and functional interference, working memory, and circulating inflammatory or neuroplasticity biomarkers. Risk of bias was assessed using the revised Cochrane risk-of-bias tool. Mean differences (MDs) with 95% confidence intervals (CIs) were pooled using random-effects models. Serum and plasma BDNF were analyzed separately. Results: Twenty-one studies were included in the systematic review, of which 15 contributed to at least one quantitative synthesis and 12 study comparisons contributed to the primary BDNF analyses. Active tDCS did not significantly affect serum BDNF (MD = −0.01 [−0.15, 0.13], p = 0.890) or plasma BDNF (MD = 0.02 [−0.25, 0.29], p = 0.870) compared with sham stimulation. In contrast, active tDCS was associated with lower pain intensity (MD = −1.79 [−2.34, −1.23], p < 0.00001). No statistically significant difference was observed in the PCS total score or in the helplessness, magnification, or rumination subscales, although the point estimates generally favored active tDCS. For pain-related disability and functional interference, active tDCS was associated with lower PCP:S total scores and lower emotional interference, whereas no significant differences were observed for interference with daily activities or pain frequency. No significant differences were observed for working memory, interleukins, tumor necrosis factor-alpha, glial cell line-derived neurotrophic factor, interleukin-18, or soluble tumor necrosis factor receptors. Substantial heterogeneity was present in several pain-related and inflammatory biomarker analyses. Conclusions: Active tDCS was not associated with consistent differences in circulating serum or plasma BDNF or in the assessed peripheral inflammatory and neuroplasticity biomarkers compared with sham stimulation; however, these null peripheral findings should not be interpreted as evidence of absent central neuroplastic effects, because circulating measures may not adequately capture localized or transient biological changes within the central nervous system. Active tDCS was associated with improvements in some pain-related outcomes; however, the limited number of studies, substantial heterogeneity, and low certainty of the available evidence preclude firm conclusions regarding its clinical effectiveness for pain management.