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Background Programmed cell death protein‐1/programmed cell death ligand‐1 (PD‐1/L1) inhibitor is a promising therapeutic option that can be used as either a first‐line or second‐line treatment for driver‐negative advanced or metastatic squamous non‐small cell lung cancers (sqNSCLC). However, reuse of PD‐1/L1 inhibitor in second‐line beyond progression after the first‐line is generally not recommended. Therefore, oncologists face challenges in making a proper decision of using PD‐1/L1 inhibitor. This analysis aimed to determine whether it is more cost‐effective to use sintilimab, a domestic anti‐PD‐1 drug in China, as a first‐line treatment than reserving it until second‐line. Methods We conducted a cost‐effectiveness analysis to compare the use of sintilimab in the first‐line setting with reserving its use until the second‐line for driver‐negative advanced or metastatic sqNSCLC from the perspective of the Chinese healthcare system. A Markov model composed of five main mutually independent health states and three temporary health states was established to simulate patients' clinical trajectory. Transition probabilities, including disease progression, survival, and adverse events‐related treatment discontinuation, were estimated using data from the ORIENT‐12, ORIENT‐3, and ALTER0303 clinical trials. The robustness of the model was assessed using deterministic sensitivity analysis (DSA) and probabilistic sensitivity analyses. Results Reserving the use of sintilimab until the second‐line was associated with a greater effectiveness (1.52 vs. 1.37 quality‐adjusted life‐years [QALYs]) and a higher healthcare cost ($12,203 vs. $14,045) compared with the first‐line sintilimab, resulting in an incremental cost‐effectiveness ratio (ICER) of $12,693 per QALY. The results of DSA suggested that variations in all parameters did not result in the ICERs surpassing the willingness‐to‐pay threshold of $35,663/QALY. Conclusions For Chinese patients with driver‐negative advanced or metastatic sqNSCLC, reserving the use of sintilimab until the second‐line represents a cost‐effective treatment strategy compared with the first‐line treatment. This finding is useful to inform Chinese healthcare policymakers regarding the optimized treatment strategies of use of domestic PD‐1/L1 inhibitors sintilimab.