Since late 2021, Omicron variants have dominated the epidemiological scenario as the most successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sublineages, driving new and breakthrough infections globally over the past two years. In this study, we investigated for the first time the host salivary response of COVID-19 patients infected with Omicron variants (BA.1, BA.2, and BA.4/5) by using an untargeted four-dimensional data-independent acquisition (4D-DIA)-based proteomics approach. We identified 137 proteins whose abundance levels differed between the COVID-19 positive and negative groups. Salivary signatures were mainly enriched in ribosomal proteins, linked to mRNAviral translation, protein synthesis and processing, immune innate, and antiapoptotic signaling. The higher abundance of 14-3-3 proteins (YWHAG, YWHAQ, YWHAE, and SFN) in saliva, first reported here, may be associated with increased infectivity and improved viral replicative fitness. We also identified seven proteins (ACTN1, H2AC2, GSN, NDKA, CD109, GGH, and PCYOX) that yielded comprehension into Omicron infection and performed outstandingly in screening patients with COVID-19 in a hospital setting. This panel also presented an enhanced anti-COVID-19 and anti-inflammatory signature, providing insights into disease severity, supported by comparisons with other proteome data sets. The salivary signature provided valuable insights into the host’s response to SARS-CoV-2 Omicron infection, shedding light on the pathophysiology of COVID-19, particularly in cases associated with mild disease. It also underscores the potential clinical applications of saliva for disease screening in hospital settings. Data are available via ProteomeXchange with the identifier PXD054133.