Background/Objectives <p>Individuals with phenylketonuria (PKU) are at increased risk for obesity, possibly due to reduced satiety induced by a PKU diet that is low protein and high carbohydrate. It is unclear how exercise alters postprandial satiety after a PKU-like meal. The objective was to examine changes in postprandial satiety, satiety hormone concentrations, energy expenditure and substrate oxidation in response to acute treadmill exercise following a PKU-like meal.</p> Subjects/Methods <p>Sixteen males (mean age [±SD]: 26.5 ± 4.8 years; BMI: 23.7 ± 3.2 kg/m²) participated in a randomized cross-over trial with two conditions: exercise and control. Both trials involved consuming a PKU-like meal comprising naturally low-protein foods, a special low-protein food and a protein substitute. In the exercise trial, participants exercised at 60% of maximal oxygen uptake for 1 h before the meal; in the control trial, they rested. Satiety agents (peptide YY [PYY], glucagon-like peptide-1 [GLP-1] and growth differentiation factor-15 [GDF-15]), appetite, energy expenditure, fat oxidation and carbohydrate oxidation were measured.</p> Results <p>Mean (±SE) appetite and postprandial PYY and GLP-1 concentrations were unaffected by exercise (<i>P</i> ≥ 0.279). However, GDF-15 was higher in the exercise trial (control: 288 ± 25 pg/mL vs. exercise: 322 ± 24 pg/mL; <i>P</i> = 0.002). Exercise increased fat oxidation (<i>P</i> = 0.013) and decreased carbohydrate oxidation post-meal (<i>P</i> = 0.022), with concomitantly lower RER (<i>P</i> = 0.005). Energy expenditure rose during exercise (<i>P</i> &lt; 0.001), but no difference occurred postprandially (<i>P</i> = 0.543).</p> Conclusions <p>Acute exercise prior to a PKU-like meal does not affect postprandial GLP-1 and PYY concentrations compared to control but GDF-15 was increased and RER was reduced, potentially improving appetite regulation.</p>