To date, chronic pain is among the most prevalent and economically burdensome chronic diseases, affecting nearly one in five individuals worldwide and costing $635 billion per year in the United States alone. Current treatments for chronic pain are limited or mildly efficacious, and some may produce adverse side effects and conditions such as drug-induced hyperalgesia or substance use disorder. Limitations of pharmacological treatments urge the development of nonpharmacological therapies for pain. Placebo effects engage the descending modulatory neural systems to induce analgesia and present a promising opportunity to study the effectiveness of nonpharmacological and noninvasive interventions for improving pain symptoms. However, not everyone will respond to a placebo treatment. Biopsychosocial factors that vary between individuals, including culture, environment, sex, and neural characteristics, may influence individual response to placebo. Therefore, understanding the mechanisms underlying the effects of biopsychosocial factors on interindividual differences in placebo effects is critical for the development of translational approaches for pain management. Here, two well-established social learning and classical conditioning paradigms were used to test the hypothesis that social, sex, and neural traits would contribute to the generation of placebo effects. The main findings of this work are threefold. First, cognitive state empathy was greater for a human demonstrator in pain compared to an avatar, and this socially induced empathy mediated subsequently induced placebo effects. Second, women exhibited larger expectations and placebo effects compared to men, and gonadal hormone levels were associated with conditioning strength, expectations, and placebo hypoalgesia. Testosterone levels were negatively associated with chronic pain severity in women, and estradiol levels in individuals with chronic pain and pain-free individuals mediated the impact of sex on expectations assessed after conditioning. These expectations mediated the impact of sex on placebo effects in individuals with chronic pain. Third, cortical morphology was positively correlated with placebo response in individuals with chronic pain. This work provides support for the careful consideration of the effects of biopsychosocial factors in the analysis and interpretation of placebo hypoalgesia studies. Importantly, these findings suggest that empathy, sex hormone, and morphological measurements can be important factors to leverage for translational and clinical approaches for chronic pain management.