Often health communication campaigns addressing misusing prescription opioids and opioid use disorder (OUD) do not pay enough attention to the associated stigma. This study investigated the effectiveness of a well-designed opioid awareness campaign on reducing stigma and provided evidence for future health communication design. CDC's Rx Awareness videos were used as the experiment material. 137 college students participated in this online experiment, and audience characteristics and video features were considered and tested. The results showed that Rx Awareness videos significantly reduced participants' stigmatizing attitudes and perceived public stigma and increased their empathy toward people with OUD. Empathy is a promising strategy to reduce opioid stigma. People with an opioid prescription history expressed more empathy. Recovery information, prescription history, and narrators' race influenced the audience's perceived public stigma. Implications for health communications and limitations of the study are discussed.