Introduction: Heavy-load free-flow resistance exercise (HL-FFRE) is a widely used training modality. Recently, low-load blood-flow restricted resistance exercise (LL-BFRRE) has gained attention in both athletic and clinical settings as an alternative when conventional HL-FFRE is contraindicated or not tolerated. LL-BFRRE has been shown to result in physiological adaptations in muscle and connective tissue that are comparable to those induced by HL-FFRE. The underlying mechanisms remain unclear; however, evidence suggests that LL-BFRRE involves elevated metabolic stress compared to conventional free-flow resistance exercise (FFRE). Aim: The aim was to evaluate the initial (<10 min post-exercise), intermediate (10–20 min), and late (>30 min) hormonal, immune, and oxidative stress responses observed following acute sessions of LL-BFRRE compared to FFRE in healthy adults. Methods: A systematic literature search of randomized and non-randomized studies was conducted in PubMed, Embase, Cochrane Central, CINAHL, and SPORTDiscus. The Cochrane Risk of Bias (RoB2, ROBINS-1) and TESTEX were used to evaluate risk of bias and study quality. Data extractions were based on mean change within groups. Results: A total of 12525 hits were identified, of which 29 articles were included. LL-BFRRE demonstrated greater acute increases in growth hormone responses when compared to overall FFRE at intermediate (SMD 2.04; 95% CI 0.87, 3.22) and late (SMD 2.64; 95% CI 1.13, 4.16) post-exercise phases. LL-BFRRE also demonstrated greater increase in testosterone responses compared to late LL-FFRE. Conclusion: These results indicate that LL-BFRRE can induce increased or similar hormone and immune responses compared to LL-FFRE and HL-FFRE along with attenuated oxidative stress responses compared to HL-FFRE.