Introduction Critical weight loss is defined as an unintentional weight loss of ≥ 5% at 1 month or ≥ 10% at 6 months from the start of treatment. Critical weight loss leads to deterioration of the immune function and reduced tolerance to treatment (surgery ± radiochemotherapy) as well as increased complication rates. Objective Critical weight loss, defined as a weight loss of ≥ 5% after 1 month or ≥ 10% after 6 months from the start of treatment, is not uncommon in head and neck cancer patients. We aimed to assess the factors associated with critical weight loss during the treatment of oral cavity squamous cell carcinoma patients. Methods A retrospective cohort study was performed at the Aga Khan University Hospital, in Karachi, Pakistan, on 125 patients. Patients receiving adjuvant therapy were considered exposed, and the outcome was critical weight loss. Results The mean age of presentation was 46.9 ± 12.8 years in patients undergoing surgery and adjuvant therapy, with 119 (79.3%) of them being male and 31 (20.7%) female. One hundred and twelve patients (81.3%) developed critical weight loss at 6 months from the start of treatment, and the only significant variable associated with critical weight loss was the stage of the disease ( p = 0.03). Conclusion A large proportion of patients with oral cancer developed critical weight loss requiring a need for intervention. The overall stage of the disease is a significant predictor of critical weight loss in patients undergoing treatment