Symptomatic Slow Acting Drugs for Osteoarthritis (SYSADOA), such as hyaluronic acid (HA), chondroitin sulfate (CS) and glucosamine (GlcN) are natural compounds, composed of repeating disaccharides, used to treat patients with osteoarthritis (OA). Many questions about the kinetics and mechanism of action of SYSADOA remain poorly answered. This review examines the data supporting oral absorption and body distribution of SYSADOA, and discusses their mechanism of action. SYSADOA are absorbed in the small intestine with a bioavailability ranging from 5 to 45% and accumulate in articular tissues. The mechanism of action of HA and CS differs in several aspects from that of GlcN. Being large molecules, HA and CS do not penetrate into chondrocytes, synoviocytes, osteoblast, osteoclast and osteocytes, and so elicit the anti-inflammatory effect by engaging membrane receptors, e.g. CD44, TLR4, and ICAM1, with a resulting dual effect: impede the fragments of extracellular matrix engaging these receptors, cause of inflammatory reaction, and block the signal transduction pathways activated by the fragments and so diminish the nuclear translocation of pro-inflammatory transcription factors. GlcN penetrates into cells by means of glucose transporters. The primary effect of GlcN is associated to its ability to O-GlcNAcylate proteins and as a consequence, modulates their activity, e.g. decrease nuclear factor-κB nuclear translocation. GlcN may also affect the transcription of pro-inflammatory cytokines by epigenetic mechanisms. The characteristics of the mechanism of action support the use of CS combined with GlcN, and suggest that HA and CS shall be more effective in initial phases of OA.