Natural gas is an abundant resource across the United States, of which methane (CH4) is the main component. About 2% of extracted CH4 is lost through leaks. The Remote Methane Leak Detector (RMLD)-Unmanned Aerial Vehicle (UAV) system was developed to investigate natural gas fugitive leaks in this study. The system is composed of three major technologies: miniaturized RMLD (mini-RMLD) based on Backscatter Tunable Diode Laser Absorption Spectroscopy (TDLAS), an autonomous quadrotor UAV and simplified quantification and localization algorithms. With a miniaturized, downward-facing RMLD on a small UAV, the system measures the column-integrated CH4 mixing ratio and can semi-autonomously monitor CH4 leakage from sites associated with natural gas production, providing an advanced capability in detecting leaks at hard-to-access sites compared to traditional manual methods. Automated leak characterization algorithms combined with a wireless data link implement real-time leak quantification and reporting. This study placed particular emphasis on the RMLD-UAV system description and the quantification algorithm development based on a mass balance approach. Early data were gathered to test the prototype system and to evaluate the algorithm performance. The quantification algorithm derived in this study tended to underestimate the gas leak rates and yielded unreliable estimations in detecting leaks under 7 × 10 − 6 m3/s (\textasciitilde1 Standard Cubic Feet per Hour (SCFH)). Zero-leak cases can be ascertained via a skewness indicator, which is unique and promising. The influence of the systematic error was investigated by introducing simulated noises, of which Global Positioning System (GPS) noise presented the greatest impact on leak rate errors. The correlation between estimated leak rates and wind conditions were investigated, and steady winds with higher wind speeds were preferred to get better leak rate estimations, which was accurate to approximately 50% during several field trials. High precision coordinate information from the GPS, accurate wind measurements and preferred wind conditions, appropriate flight strategy and the relative steady survey height of the system are the crucial factors to optimize the leak rate estimations.