Engine calibration requires detailed feedback information that can reflect the combustion process as the optimized objective. Indicated mean effective pressure (IMEP) is such an indicator describing an engine’s capacity to do work under different combinations of control variables. In this context, it is of interest to find cost-effective solutions that will reduce the number of experimental tests. This paper proposes a random forest machine learning model as a cost-effective tool for optimizing engine performance. Specifically, the model estimated IMEP for a natural gas spark ignited engine obtained from a converted diesel engine. The goal was to develop an economical and robust tool that can help reduce the large number of experiments usually required throughout the design and development of internal combustion engines. The data used for building such correlative model came from engine experiments that varied the spark advance, fuel-air ratio, and engine speed. The inlet conditions and the coolant/oil temperature were maintained constant. As a result, the model inputs were the key engine operation variables that affect engine performance. The trained model was shown to be able to predict the combustion-related feedback information with good accuracy (R2 ≈ 0.9 and MSE ≈ 0). In addition, the model accurately reproduced the effect of control variables on IMEP, which would help narrow the choice of operating conditions for future designs of experiment. Overall, the machine learning approach presented here can provide new chances for cost-efficient engine analysis and diagnostics work.