Individuals who are deaf and use American Sign Language (ASL) as their primary mode of communication experience unique negative life experiences, such as lack of communication, limited access to services, marginalization, and discrimination, that can adversely impact resilience and psychological well-being. In addition, deaf individuals experience higher rates of intimate partner violence, polyvictimization, sexual, physical, and emotional abuse, and unemployment. These negative life experiences can sometimes be accompanied by maladaptive behaviors, such as substance use. Resilience and a positive sense of well-being can help to mitigate adverse life events. This survey research utilizes a sample of 206 deaf participants, whose primary language is ASL, and hearing participants to examine the relationships between negative life experiences, substance use, resilience, and well-being. Findings indicate: (1) deaf participants reported experiencing several negative life events significantly more often than their hearing counterparts, specifically being sent to jail or prison, having a serious physical illness, and sexual abuse by a partner than hearing participants; (2) deaf participants reported more experiences of having an abortion or miscarriage and parental separation or divorce as children than their hearing counterparts; (3) deaf individuals reported higher marijuana use than their hearing counterparts, but less use of stimulants, inhalants, and prescription drug abuse; (4) experiences of mental illness was significantly associated with resilience and well-being; and (5) deaf and hearing participants had similar scores in resilience and well-being. The author identifies strengths and limitations of the study and discusses implications for future research.