Human behavioral studies have shown that reward has multifaceted (motivational, learning, and emotional) effects on cognitive control. Past studies have extensively explored the neural underpinning of the motivational effect of reward on cognitive control, but less is known on the other components. The present study investigates the learning effect of reward on cognitive control with a novel paradigm reinforcing task-irrelevant stimulus–response (S-R) associations. We manipulated the contingency of irrelevant spatial stimulus–response–reward between participants (n = 54) in an orthogonal Simon task during EEG recording. The behavioral results showed that the orthogonal Simon effect in RTs and error rates increased or reversed when performance-contingent reward always followed spatially compatible or incompatible trials. The EEG results showed that the initial incorrect activation of the lateralized readiness potential, reflecting response preparation based on irrelevant spatial S-R associations, was present in the incompatible or compatible condition when reward always followed compatible or incompatible trials. Meanwhile, the P3b amplitude also showed a similar pattern of increase or reversal depending on the contingency of irrelevant stimulus–response–reward. These findings suggest that the brain used reward-strengthened irrelevant spatially compatible or incompatible S-R associations to predict responses. Moreover, the frontocentral N2 amplitude and theta band (4–8 Hz) power showed similar reward-related increase or reversal in the conflict effect, suggesting that there was conflict when the response predicted by the reward-strengthened irrelevant S-R associations was different from the correct response. Taken together, these results suggest that reinforcement learning of irrelevant spatial S-R associations can modulate cognitive control.