Many practical cases with waste heat recovery potential such as exhaust gases of reciprocating engines, cement kilns or heat-treating furnaces, are nowadays often integrated with organic Rankine cycle to convert waste heat to the mechanical power. However, when dealing with high-temperature waste heat, organic Rankine cycle faces efficiency limit due to the physical properties of the working and thermal fluids. That gives room for further enhancement of the waste heat recovery technologies via the investigation of different non-conventional schemes as one of the possible ways. In the present work, a system introducing the combined inverted Brayton plus organic Rankine cycle is under investigation. Aspen Hysys models of both conventional organic Rankine cycle and combined cycle were designed, orienting on waste heat recovery from the heavy-load gas-fueled reciprocating engine exhaust. In this way, the performance of the combined scheme was benchmarked versus the conventional organic Rankine cycle. An assessment of the organic Rankine cycle working fluids was provided, and pentane has shown the best thermodynamic performance. The study on inverted Brayton cycle defined the remarkable effect of the water condensation in the gas duct on the inverted Brayton cycle performance. Finally, both thermodynamic and economic optimizations of the models were conducted, setting the stage for the comparison of solutions. Results have shown the 10% advantage of the combined scheme over organic Rankine cycle in generated power and system efficiency. The levelized-cost-of-energy-based optimization for variable capacity factors has highlighted above 6% advantage of the investigated solution. The analysis of the sensitivity from machines’ efficiencies and heat exchangers’ pinches has shown that with some sets of parameters, the studied scheme may concede to the organic Rankine cycle.