Background: Chronotherapy in cancer is optimizing the administration time of anti-cancer treatment according to circadian rhythm and cellular phase to improve the efficacy against tumor cells while decreasing side effects on normal cells. Several randomized controlled trials (RCT) evaluated chronotherapy of chemotherapy (chrono-chemotherapy: time-specific infusions) and/or radiotherapy (chrono-radiotherapy: morning radiotherapy) in various cancers and reported improved treatment efficacy and reduced toxicity. However, the effect of chronotherapy in HNC treatment is unclear as there are no prior systematic reviews reported. Therefore, this systematic review summarizes available clinical evidence on the effect of chrono-chemotherapy (CCT) and chrono-radiotherapy (CRT) on treatment response and adverse events in HNC adult patients. Methods: We conducted a systematic search using Medical Subject Headings (MeSH) in four online databases (OVID, Embase, CINAHL and Scopus), and 6078 articles identified were published in English between the databases' inception date and June 30, 2022. We included original peer-reviewed retrospective and prospective human studies investigating CCT and/or CRT versus conventional treatments in HNC patients. We excluded articles that contained no abstract, were unrelated to HNC, were pre-clinical and case reports, or did not include time-specific interventions in their methods. Results: 16 studies were finally included. Overall, studies were heterogenous in demographics, study design, intervention, and outcome measures, thus meta-analysis could not be performed. Nine studies (RCT = 3, Non-RCT = 2 & Retro = 4) investigated CRT. Squamous cell carcinoma (SCC) was mainly reported as the primary tumor (stage I-II). 7/9 studies reported a significant reduction in the incidence of oral mucositis (Grade ≥3) in the CRT group as opposed to conventional radiotherapy (RT) groups (p < 0.05). In contrast, treatment response was investigated in 4/9 studies and was insignificant (p > 0.05). Seven studies (RCT = 5 & Retro = 2) investigated CCT in patients diagnosed with SSC (stage II-IV). All included studies had concurrent RT. Different chemotherapeutic agents were used in combinations or as a single agent, namely Cisplatin, 5- Fu, Paclitaxel and Docetaxel. CCT groups in all studies achieved a significant reduction in Nausea & Vomiting (Grade ≥3), while a significant reduction in Leukopenia & Thrombocytopenia (Grade ≥3) was reported in 2 studies only (p < 0.05). Treatment response (OS and PFS) was not significantly different (p > 0.05) between both groups except 2 studies reported significantly higher ORR in chronotherapy groups (p < 0.05). Conclusions: CCT and CRT in HNC treatment in most studies provided evidence of toxicity reduction while treatment response was maintained. However, large multicentric randomized controlled studies with standardized protocols and optimized designs are still needed.