Previously, perceived exertion in submaximal resistance exercise protocols was reported to be affected by the intensity of load followed by work-to-rest ratio. Nevertheless, the effect of set configuration, which entails the metabolic, hormonal, and neuromuscular implication of the session is currently unknown, despite that perceived exertion discriminates these differences. We aimed to analyze the effect of three submaximal set configurations on perceived exertion and their relationship with velocity as a mechanical measure of fatigue. Seventeen healthy subjects (23 ± 2 years) performed with the 10RM load on the leg press (211 ± 45 kg) a total of 40 repetitions with 720 seconds of rest in three randomized experimental sessions with the same work-to-rest ratio. The sessions consisted of an inter-repetition rest design performing individual repetitions, a cluster design performing groups of four repetitions, and a traditional design performing groups of eight repetitions. At the end of the session, the non-parametric ANOVA-type test revealed differences between protocols (p < 0.001), with lower values of perceived exertion in the inter-repetition rest design in comparison with the cluster design (p = 0.003) and traditional design (p < 0.001). Additionally, Spearman rank correlations (p < 0.001) were observed for the inter-repetition rest design (rho = -0.72) and traditional design (rho = -0.8) between perceived exertion and velocity. Our findings suggest that the submaximal set configuration is a determinant of perceived exertion by itself and that perceived exertion represents similar mechanisms as velocity, such as fatigue and certain characteristics of the session and the individual.