People with serious mental illness (SMI) are often troubled by societal stigma and subsequent processes, including self-stigma and lowered self-efficacy. Previous studies have observed the interrelationship among social stigma, general self-efficacy, psychiatric symptom severity, and self-stigma. Yet, it is warranted to examine the processes through which social stigma can hamper self-efficacy. This cross-sectional cohort study aimed to examine symptom severity and self-stigma as potential mediating factors between societal stigma and general self-efficacy. Three hundred working-age adults with self-reported SMI completed a Qualtrics survey that consists of measures of interested variables. Serial mediation analyses were used to examine the relationship. Symptom severity and self-stigma fully mediate the relationship between societal stigma and general self-efficacy. The implications of these results are that mental health professionals can target self-stigma and symptom severity to mitigate the negative effects of social prejudice and discrimination on general self-efficacy.