Background: The leg press is one of the most typical exercises for strengthening the lower limbs. The objectives of this study were to compare 5 inclined leg press exercise conditions, varying the feet width stance (100% or 150% hip width), the feet rotation (0° or 45° external rotation) on the footplate and using 2 different movement velocities (MVs; maximum intended, and 2:2 seconds steady-paced velocities) to determine their effect on muscle activation as well as on the kinematic parameters between trained men and trained women. Hypotheses: There will be no significant differences in muscle activation with regard to the feet position. The higher the MV, the greater the muscle activation. Study Design: A cross-sectional cohort study. Level of Evidence: Level 3. Methods: A repeated-measures between-group design was performed to examine muscle activation and kinematic parameters for the different conditions between gender groups. The level of significance was set at alpha = 0.05 for all statistical analyses. Results: Muscle activation presented no differences between conditions regarding feet width stance or feet rotation. Furthermore, muscle activation was greater during positive phases than negative phases of the exercise for all conditions and was also greater under maximum intended velocity conditions compared with steady-paced conditions. Otherwise, the muscle activation pattern presented slight differences by gender. In men, the greatest muscle activation was for the vastus medialis, followed by the vastus lateralis (VL), rectus femoris (RF), and gluteus medialis (GMED), while in women, the greatest muscle activation was for the vastus medialis, followed by the RF, VL, and GMED. Finally, greater mean propulsive velocity, maximum velocity, maximum power, and footplate displacement values were reported for men than for women under all the conditions. Conclusion: The inclined leg press exercise produces the highest muscle activation in the vastus medialis, regardless of the velocity, feet stance, or gender. Clinical Relevance: Given that there are no differences in muscle activation regarding the feet stance, a participant’s preferred feet stance should be encouraged during the inclined leg press exercise. Furthermore, the MV would preferably depend on the session objective (a training or a rehabilitation program), being aware that there is greater muscle activation at higher speeds. The inclined leg press exercise could be performed as a closed kinetic chain exercise when the main objective is to activate the vastus medialis.