Background Lactate dehydrogenase (LDH) is involved in the Warburg effect. Elevated serum LDH is a prognostic marker for metastatic solid cancer. Aim To investigate the prognostic impact of serum LDH in patients with head and neck squamous cell carcinoma treated with immune checkpoint inhibitors (ICIs). Materials and Methods This retrospective study included 129 patients treated with ICIs between 2017 and 2023. The effects of pretreatment LDH, LDH at 3 months, and change in LDH during the first 3 months (ΔLDH) on overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan–Meier method and Cox regression model. Results The 1-year PFS and OS rates for high and low groups were 6.0% and 30.1% for pretreatment LDH (p = 0.044), 25.7% and 38.3% for on-treatment LDH (p = 0.079), and 14.3% and 38.7% for ΔLDH (p = 0.008), as well as 42.1% and 60.9% for pretreatment LDH (p = 0.109), 56.0% and 80.5% (p < 0.001) for on-treatment LDH, and 31.0% and 81.0% for ΔLDH (p < 0.001), respectively. ΔLDH was an independent prognostic factor for both PFS and OS. Conclusions and Significance ΔLDH can be used to predict ICI treatment outcomes and as a marker in deciding to continue ICI therapy.