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Purpose: To describe the efficacy of autologous serum (AS) eye drops to reverse severe contact lens (CL)-induced limbal stem cell (LSC) deficiency (LSCD). Methods: This is a prospective, uncontrolled, interventional case series that enrolled 20 eyes of 14 consecutive patients diagnosed with severe CL-induced LSCD at presentation, based on clinical examination, at a tertiary referral center for the period December 2016 to December 2018. All eyes underwent AS treatment for at least 2 weeks with a follow-up for at least 2 months. Demographic data and treatment outcomes were collected and analyzed. Results: The mean patient age at presentation was 30.5 years (range, 19–49 years). The mean duration of soft contact lens wear was 15.6 years (SD, 7.58 years; range, 5–31 years). All study eyes had pain and blurred vision at presentation. All eyes had recurrent or persistent corneal epithelial defect, stromal scarring and opacity, and superficial vascularization and peripheral pannus at presentation. Aggressive treatment with AS succeeded in all eyes. Signs and symptoms of LSCD stabilized in all eyes within 2 weeks and resolved in 6 eyes (30.0%) in 2 weeks, 9 eyes (45.0%) in 4 weeks, and 5 eyes (25.0%) in 8 weeks. The mean follow-up time was 9.45 ± 1.79 weeks (range, 8–24 weeks). Conclusions: Early identification and aggressive treatment of the ocular surface disease with AS can medically reverse severe CL-induced LSCD and prevent the need for surgical intervention.