Plasma is the most frequently clinically used body fluid sample, characterized by noninvasive sampling, convenient to use, and rich contents, and is an important source sample for the excavation of potential biomarkers related to the disease. Low molecular weight proteins and peptides (LMWPs) in plasma include cytokines, growth factors, peptide hormones, and protein degradation products, which are favored by researchers because of their small molecular weight, measurable sequence information, and wide sources. In recent years, the studies on LMWPs have made new progress with the rapid development of high-resolution, high-sensitivity mass spectrometers and computational science, and the integration of new technologies and new methods. This review introduces the classification of plasma LMWPs, including small intact proteins, protein degradation products, neuropeptides, immunopeptides, carrier protein-bound peptides, and sORF-encoded peptides, based on the current research hotspots in this field. In addition, it also summarizes the research progresses on enrichment strategies, functional studies, and disease-related biomarkers. Finally, the challenges and future research direction of plasma LMWPs are discussed.