Neuroprotective factors are involved in brain functioning. Although physical exercise has been shown to have a positive influence on these factors, the effect of resistance exercise on them is not well known. This systematic review and meta-analysis aimed to 1) estimate the efficacy of resistance exercise on major neuroprotective factors, such as insulin-like growth factor-1 (IGF-1), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF), in middle and late life and 2) determine whether the effect is dose dependent. A systematic search was conducted in CINAHL, Cochrane CENTRAL, MEDLINE, Scopus, PEDro, SPORTDiscus, and Web of Science up to November 2022. Random effects models were used to estimate standardized mean differences (SMDs) and their respective 95% confidence intervals (CI) for the effect of resistance exercise on peripheral IGF-1, BDNF or VEGF levels in older adults. Thirty randomized clinical trials with 1247 subjects (53.25% women, 45-92 years) were included in the systematic review, and 27 were selected for the meta-analysis. A significant effect of resistance exercise on IGF-1 levels was observed (SMD: 0.48; 95% CI: 0.27, 0.69), being more effective when performing 3 sessions/week (SMD: 0.55; 95% CI: 0.31, 0.79) but not on BDNF (SMD: 0.33; 95% CI: -0.29, 0.94). The effect on VEGF could not be determined due to the scarcity of studies. Our data support the resistance training recommendation in middle and late life, at a frequency of at least 3 sessions/week, to mitigate the neurological and cognitive consequences associated with aging, mainly through IGF-1.