Our team evaluated contrast enhancement for portal imaging using Monte Carlo simulation in nanoparticle-enhanced radiotherapy. Dependencies of percentage contrast enhancement on flattening-filter (FF) and flattening-filter-free (FFF) photon beams were determined by varying the nanoparticle material (gold, platinum, iodine, silver, iron oxide), nanoparticle concentration (3–40 mg/mL) and photon beam energy (6 and 10 MV). Phase-space files and energy spectra of the 6 MV FF, 6 MV FFF, 10 MV FF and 10 MV FFF photon beams were generated based on a Varian TrueBeam linear accelerator. We found that gold and platinum nanoparticles (NP) produced the highest contrast enhancement for portal imaging, compared to other NP with lower atomic numbers. The maximum percentage contrast enhancements for the gold and platinum NP were 18.9% and 18.5% with a concentration equal to 40 mg/mL. The contrast enhancement was also found to increase with the nanoparticle concentration. The maximum rate of increase of contrast enhancement for the gold NP was equal to 0.29%/mg/mL. Using the 6 MV photon beams, the maximum contrast enhancements for the gold NP were 79% (FF) and 78% (FFF) higher than those using the 10 MV beams. For the FFF beams, the maximum contrast enhancements for the gold NP were 53.6% (6 MV) and 53.8% (10 MV) higher than those using the FF beams. It is concluded that contrast enhancement for portal imaging can be increased when a higher atomic number of NP, higher nanoparticle concentration, lower photon beam energy and no flattening filter of photon beam are used in nanoparticle-enhanced radiotherapy.