Background: This study aimed to compare acute hemodynamic, metabolic (glucose and blood lactate concentrations), hormonal (growth hormone and normetanephrine), heart rate variability (HRV), and rating of perceived exertion (RPE) responses before and after bouts of a boxing exergame with and without blood flow restriction (BFR) in non-athlete young individuals. Methods: Fourteen participants (age: 30 ± 10 y; BMI: 21 ± 3 kg.m−2) participated in two sessions of a 20 min boxing exergame. During week one, the participants were randomly divided into two groups and played against one another under normal (n = 7) and BFR (n = 7) conditions. Over the next exercise session, participants were then reallocated to the opposite condition (normal vs. BFR) for data collection. Hemodynamic, metabolic, HRV, and hormonal parameters were measured before and immediately after the exercise protocols. Results: Playing exergame led to a significant increase in hemodynamic variables (except for diastolic blood pressure) regardless of BFR condition with no between-group differences. Regarding HRV, significant reductions in total power (TP) and low-frequency (LF) waves were identified in the non-BFR group (p < 0.0001) compared with the BFR group. Conversely, a significant increase in very LF (VLF) waves was noted for the BFR group (p = 0.050), compared with the non-BFR group. Significant increases were observed in serum concentrations of growth hormone, normetanephrine, and blood lactate concentration from pre- to post-exercise under both conditions (p ≤ 0.05), with no significant differences between the groups. Moreover, no statistically significant changes were observed in glucose levels. RPE responses were significantly greater (p ≤ 0.05) in the BFR group compared with the non-BFR group throughout the exercise session. Conclusions: We observed similar hemodynamic, hormonal, and metabolic responses after an acute boxing exergame session in young individuals, whether conducted with or without BFR. However, notable differences were observed in certain HRV markers and RPE. Specifically, the inclusion of BFR resulted in an elevation of VLF and a heightened perceived exertion. These findings suggest that BFR may alter cardiac autonomic and perceptual responses during exergaming. Further research is warranted to understand the long-term implications and potential benefits of incorporating BFR into exergaming routines.