Objectives Brain-derived neurotrophic factor (BDNF) has been shown to increase in an intensity dependent manner in response to aerobic exercise. However, previous research investigating the use of resistance exercise to increase BDNF levels has been less conclusive, likely due to the low intensity nature of traditional resistance exercise programs. This study examined the influence of acute resistance exercise to-fatigue on serum BDNF levels and blood lactate. Design Acute crossover study. Methods Eleven untrained to intermediately trained males (age: 25.0 ± 1.3 year) and five untrained females (age: 23.2 ± 1.1 year) were recruited to undertake two bouts of resistance exercise. Strength (five sets of five repetitions, 180 s recovery) and hypertrophy (three sets of ten repetitions, 60 s recovery) based resistance exercise was implemented to-fatigue to examine the effect on serum BDNF and blood lactate levels immediately post-, and 30 min post-exercise. Results An interaction (p < 0.01; ES = 0.52) was observed between conditions immediately post-exercise, with hypertrophy resulting in significantly greater BDNF levels when compared with strength exercise. Changes in lactate and BDNF from baseline to post- exercise were positively correlated following hypertrophy exercise (r = 0.70; p < 0.01), but not correlated following strength exercise (r = 0.18; p = 0.56). Conclusions The use of a to-fatigue hypertrophy based resistance exercise protocol provides the necessary stimulus to increase peripheral serum BDNF. Mechanistically, the presence of lactate does not appear to drive the BDNF response during resistance exercise.