Objectives As a pivotal part of precision therapy, PD‐1/PD‐L1 immunotherapy has been gradually used in head and neck cancer (HNC). We investigated the effect and adverse events of PD‐1/PD‐L1 inhibitors alone or with conventional therapy. Design The groups using PD-1/PD-L1 immunotherapy or combining with conventional therapy were defined as the experimental groups, while the standard of care were the control groups. Cochrane Library, Embase, PubMed, and Web of Science were undertaken to identify literature up to November 20, 2020. Overall survival (OS) and progression-free survival (PFS) were the primary outcome measures. Secondary outcome measures included objective response rate (ORR), disease control rate (DCR), any grade and grade≥3 adverse events (AE). Results Five randomized controlled trials (RCTs) and nine single-arm trials were included in the systematic review. The OS of the experimental groups was better than the control groups (OR = 0.63, 95%CI: 0.49‐0.82, I²=35%, P=0.0004), particularly in patients who smoke current/former or with human papillomavirus negative (HPV-). The experimental groups had longer OS than the control groups in patients with PD-L1 positive (OR = 0.75, 95% CI: 0.65‐0.85, I²=0%, P<0.0001). Patients with HPV positive (HPV+) had more favorable OS than those with HPV- (OR = 0.56, 95%CI:0.44-0.71, I²=39%, P<0.00001). There were statistical differences in AEs (e.g., fatigue, rash, hypothyroidism, etc.) and no statistical differences in PFS, ORR, and DCR. Conclusion PD-1/PD-L1 immunotherapy or combining with conventional therapy can improve the treatment effect and induce fewer adverse events of digestion and blood system, except for hypothyroidism.