A super-saturated self-nanoemulsifying drug delivery system (super-SNEDDS), containing the poorly water-soluble drug halofantrine (Hf) at 150% of equilibrium solubility (S eq), was compared in vitro and in vivo with a conventional SNEDDS (75% of S eq) with respect to bioavailability and digestibility. Further, the effect of digestion on oral absorption of Hf from SNEDDS and super-SNEDDS was assessed by incorporation of the lipase inhibitor tetrahydrolipstatin (orlistat) into the SNEDDS. The SNEDDS contained soybean oil/Maisine 34-I (1:1), Kolliphor RH40, and ethanol at a ratio of 55:35:10, w/w percent. For the dynamic in vitro lipolysis, the precipitation of Hf at 60 min was significantly larger for the super-SNEDDS (66.8 ± 16.4%) than for the SNEDDS (18.5 ± 9.2%). The inhibition of the in vitro digestion by orlistat (1% (w/w)) lowered drug precipitation significantly for both the super-SNEDDS (36.8 ± 1.7%) and the SNEDDS (3.9 ± 0.7%). In the in vivo studies, the super-SNEDDS concept proved valid in a rat model with a significantly larger C max for the super-SNEDDS (964 ± 167 ng/mL) than for the SNEDDS (506 ± 112 ng/mL). The bioavailability of Hf dosed in super-SNEDDS (32.9 ± 3.6%) and SNEDDS (22.5 ± 6.3%) did not change significantly with co-administration of orlistat (45.5 ± 7.3% and 21.9 ± 6.5%, respectively). However, the pharmacokinetic parameters changed; the t max of the super-SNEDDS (1.3 ± 0.1 h) and SNEDDS (2.8 ± 1.2 h) were significantly lower when dosed with orlistat (6.0 ± 1.3 and 6.3 ± 1.2 h, respectively). These findings suggest that the role of lipid digestion for the absorption of drugs from SNEDDS may be less important than previously thought.