The present study examined the effect of Acetaminophen on the painful experience of social rejection by examining brain, cardiac and behavioral measures reflecting different aspects of social feedback processing. Healthy students (N = 72), after ingesting either Acetaminophen or a placebo, performed a social judgment paradigm (SJP), in which they could be expectedly or unexpectedly rejected or accepted. During the task, cardiac and brain responses to different types of feedback were measured, as well as expectancies relating to the given feedback. Enhanced cardiac deceleration was found after unexpected social rejection as compared to all other conditions. Larger mean P3 amplitude was found after expected positive and negative feedback stimuli as compared to unexpected stimuli. While cardiac deceleration and P3 were not affected by Acetaminophen, behavioral responses were. While in the control group the percentage of acceptance predictions decreased over the experiment (learning from negative feedback), the Acetaminophen group did not adjust their positive prediction bias over time. The unexpected effect of Acetaminophen on prediction behavior suggests that Acetaminophen might indeed play a role in social pain perception. The normally observed social pain-based learning effect seems to disappear when participants ingest Acetaminophen, which can be interpreted as a reduced pain perception after Acetaminophen.