Only a limited amount of orally administered lipid nanoparticles are absorbed as intact particles due to lipolysis by lipases in the gastrointestinal tract. It is hypothesized that by counteracting lipolysis, more particles will survive gastrointestinal digestion and be absorbed as intact particles. In this study, incorporation of a lipase inhibitor orlistat (OLST), as well as polyethylene glycol (PEG) coating, is employed to slow down the lipolysis using solid lipid nanoparticles (SLNs) as model particles. To explore the in vivo behaviors of the particles, near-infrared fluorescent probes with absolute aggregation-caused quenching (ACQ) properties are used to label and track the unmodified, PEG-coated and OLST-loaded SLNs. The in vitro lipolysis study indicates very fast first-order degradation of unmodified SLNs and significantly decreased degradation of OLST-SLNs. Live imaging reveals the same trend of slowed-down lipolysis in vivo which correlates well with the in vitro lipolysis. The scanning of ex vivo gastrointestinal segments confirms the considerably prolonged residence time of OLST-SLNs, mirroring the significantly decreased lipolysis rate. The observation of fluorescence in the blood, though very weak, and in the liver speaks of the oral absorption of intact SLNs. The substantially higher hepatic levels of OLST-SLNs than unmodified SLNs should be attributed to the significantly enhanced survival rate because both particles exhibit similar cellular recognition as well as similar physicochemical properties except for the survival rate. Similarly, slowing down lipolysis also contributes to the significantly enhanced cumulative lymphatic transport of OLST-SLNs (7.56% vs. 1.27% for the unmodified SLNs). The PEG coating slows down the lipolysis rate as well but not to the degree as done by OLST. As a result, the gastrointestinal residence time of PEG-SLNs has been moderately prolonged and the hepatic levels moderately increased. The weakened cellular recognition of PEG-SLNs implies that the enhanced oral absorption is solely ascribed to the slowed-down lipolysis and enhanced mucus penetration. In conclusion, the oral absorption of intact SLNs can be significantly enhanced by slowing down lipolysis, especially by OLST, showing potential as carriers for the oral delivery of labile biomacromolecules.