Although it is clear that most people attempt to avoid pain and often find it unpleasant in the moment, research suggests that changes in affect after pain are not universally negative. To help advance our understanding of pain–affect relationships, the goal of the current study was to conduct a meta-analysis of studies examining changes in negative affect, as defined by subjective experience and psychophysiology, after the experience of acute laboratory pain. We identified 22 effect sizes from 17 different studies (N = 1,717). We tested several different hypotheses based primarily on theories of nonsuicidal self-injury (NSSI), with mixed support. Our main findings were that pain had a small to medium effect in reducing negative affect (dav = −0.35, 95% confidence interval [CI] [−0.58, −0.12]), and most robustly regulated negative affect in the context of a negative affect induction (dav = −0.37, 95% CI [−0.73, −0.02]) relative to neutral affect induction (dav = 0.08, 95% CI [−0.09, 0.26]). Similar reductions were also seen after painful and nonpainful stimulation, calling into question whether pain is necessary or whether any stimulation is sufficient. The results lead to several questions to be addressed in future research.