Cefuroxime axetil (CA) is an oral cephalosporin which hydrolyzes rapidly to the active parent compound cefuroxime. CA is known to have incomplete oral bioavailability (30–50%) due to its poor solubility and enzymatic conversion to cefuroxime in the gut lumen. In order to overcome these drawbacks, a lipid-based self-nanoemulsifying drug delivery system (SNEDDS) has been developed and optimized. The SNEDDS formulations were prepared using the aqueous phase titration method. The greatest self-emulsifying area was found in the 2:1 Smix ratio. As a result, different SNEDDS formulations were carefully selected from this phase diagram based on their smaller droplet size < 100 nm, polydispersity index ≤ 0.5, dispersibility (Grade A), and transmittance (%) > 85%. Thermodynamic stability tests were carried out in order to rule out any metastable/unstable SNEDDS formulations. The droplet size, polydispersity index, zeta potential, and entrapment efficiency (% EE) of optimized CA-loaded SNEDDS (C-3) were 18.50 ± 1.83 nm, 0.064 ± 0.008, −22.12 ± 1.20 mV, and 97.62 ± 1.06%, respectively. In vitro release studies revealed that the SNEDDS formulation had increased CA solubility. CA-SNEDDS-C3 increased CA cellular uptake, possibly due to increased CA solubility and the inhibition of enzymatic conversion to cefuroxime. Finally, in terms of the improvement of oral bioavailability, CA-loaded-SNEDDS could be a viable alternative to commercially available CA formulations.