Objectives Previous network meta-analysis (NMA) demonstrated advantageous or similar efficacy of baloxavir marboxil (baloxavir) over neuraminidase inhibitors in otherwise healthy (OwH) influenza patients. This analysis assessed the efficacy and safety of baloxavir in the subgroup of high-risk (HR) patients and in the population of uncomplicated influenza consisting of OwH and HR patients with influenza. Methods A systematic literature review (SLR) was performed in Medline, Embase, CENTRAL and ICHUSHI up to August 8th, 2018. A Bayesian NMA was conducted to compare baloxavir with oseltamivir, zanamivir, laninamivir and peramivir in HR patients and all uncomplicated patients. Results Based on the SLR, a total of 32 studies were identified as pertinent for the analysis, including 7 studies on HR patients, 13 trials on OwH patients and 14 studies on OwH?+?HR population. NMA of 10 trials assessing HR patients demonstrated comparable time to alleviation of symptoms for all treatments. Mean decline in virus titer from baseline at 24h after treatment was significantly greater for baloxavir compared with oseltamivir and peramivir. The risks of total complications and drug-related adverse events were comparable between baloxavir and zanamivir, oseltamivir and laninamivir. These findings were highly consistent with results of the NMA using pooled evidence on the uncomplicated population of OwH and HR patients. Conclusions Baloxavir was significantly more effective than placebo regarding all outcomes except for the risk of pneumonia. Besides, baloxavir was associated with similar clinical efficacy and safety, and superior antiviral activity compared to other antivirals in HR patients, as well as in the entire population of uncomplicated patients with influenza.