This study examines how stigmatizing messages about opioids influence beliefs, emotions, attitudes, and behaviors. Uniting the model of stigma communication (MSC) and intergroup emotions theory (IET) along with persuasion and stigma research, this study proposed a new identity-based model of stigma message effects: the integrative model of identity-based stigma communication (I-MISC). The experimental study among 1,444 U.S. MTurk participants tests the proposed mediators and moderators put forth in the I-MISC and offers theoretical and practical implications related to stigma communication theory and opioids stigma communication. The I-MISC argues that stigma messages can lead to stigma-related outcomes through dual affective and cognitive pathways. In other words, stigma messages can cause harm because those messages trigger negative emotional reactions or belief-based perceptions. More specifically, the I-MISC situates stigma beliefs and negative affect or emotions as these dual mediators that can operate in tandem or separately to influence stigma outcomes. Affective mediators explored in this study include negative affect, anger, frustration, fear, disgust, anxiety, sadness, and sympathy. Cognitive mediators explored in this study include stigmatizing beliefs about opioids related to beliefs about dangerousness, immorality, and responsibility. In addition, experience with Opioid Use Disorders (OUDs) was explored as a moderator of the relationship between stigma messages and emotional responses. Five outcomes of the stigma process were considered: attitudes, social distance, behavioral regulation, support for opioid-related policies, and stigma message sharing. Results of a 4 (stigma message feature: mark, label, responsibility, peril) x 2 (stigma level: high, low) x 3 (opioid context: prescription opioids, fentanyl, heroin) between subjects online experiment offered preliminary support for the I-MISC. Mark and peril messages exerted the strongest effects, with null findings for label and responsibility messages. Mark and peril messages each exerted indirect effects on all five study outcomes, through primarily a combination of cognitive and affective pathways, leading to less positive attitudes, more desired social distance, increased behavioral regulation, less support for helpful opioid-related public policies, and more stigma message sharing. Affective mediation varied based on an individual’s experience with OUDs. This research suggests the importance of removing stigmatizing communication about opioids in health and news media messaging.