This paper presents a novel least squares-based calibration method for addressing misalignment errors in low-cost unmanned aerial vehicles (UAVs) onboard electro-optical pods. Initially, the impact of pod misalignment error on target positioning accuracy is rigorously analyzed through numerical simulation. Subsequently, to address the issue of inaccurate target positioning stemming from pod misalignment error in low-cost UAVs, a simplified model of the UAV coordinate transformation system is introduced. This model effectively isolates the pod misalignment errors, enabling the development of a least squares-based calibration method for rapid error correction. Additionally, a calibration approach is devised with the aim of decoupling body attitude angle errors and pod frame angle errors, thereby further mitigating error sources within the measurement matrix and enhancing calibration precision. Simulation results show the effectiveness of the approach, with over 80% of pod misalignment errors reduced to within 0.5° through ground calibration. This underscores the algorithm’s capability to accurately calibrate pod misalignment errors under static ground conditions for a mass of UAVs.