Research examining the changes in muscle oxygen saturation across multiple sets of resistance exercise is limited. The purpose of this study was to describe the physiological response of muscle oxygenation parameters during upper-body resistance exercise and examine the differential effects of relevant participant characteristics on resistance training performance and muscle oxygen saturation dynamics. Sixty-one recreationally trained men (n = 44; 21.8 ± 2.6 years) and women (n = 17; 20.2 ± 1.8 years) completed five-repetition maximum sets of barbell bench presses at a load equal to 75% 1-RM with a 2 min rest interval. Muscle oxygen saturation (SmO2) dynamics within the anterior deltoid were monitored using a portable near-infrared spectroscopy sensor. The percent change in SmO2 (∆%SmO2), the muscle oxygen re-saturation rate (SmO2RecSlope), and the highest measured SmO2 value during recovery periods (SmO2Peak) were measured. Two-way (sex [men, women] x time [sets 1–5]) repeated measures analyses of variance (ANOVA) were performed on muscle saturation variables. To examine the effect of relevant controlling variables, separate analyses of covariance (ANCOVA) with repeated measures were also performed. No differences were seen with ∆%SmO2 across sets. The main effects for sets occurred for SmO2RecSlope, whereby a decline was noted on sets 4 and 5 (p = 0.001) compared to set 1. Additionally, SmO2Peak was the lowest on set 5 (p < 0.001) compared to all other sets. Moreover, body mass (p = 0.013), diastolic blood pressure (p = 0.044), and mean arterial pressure (p = 0.033) for ∆%SmO2 were the only significant covariates noted amongst the muscle oxygenation variables. In conclusion, no sex differences and only a few set differences in muscle oxygen saturation dynamics were seen without employing any covariates. Body mass, diastolic blood pressure, and mean arterial pressure were identified as factors that could influence observed responses.