Taking the Luding Ms6.8 earthquake (EQ) on 5 September 2022 as a case study, we investigated the potential seismic anomalies of the ionosphere, infrared radiation, atmospheric electrostatic field (AEF), and hot spring ions in the seismogenic region. Firstly, we analyzed the multi-parameter anomalies in the ionosphere around the epicenter and found synchronous anomalous disturbances in the ground parameters, namely the global ionospheric map (GIM), GPS, TEC, and satellite parameters, such as the He+ and O+ densities on 26 August under relatively quiet solar–geomagnetic conditions (F10.7 < 120 SFU; Kp < 3; Dst > −30 nT; |AE| < 500 nT). Next, both the anomaly analysis of the infrared radiation and AEF, and the survey results of the Luding EQ scientific expedition on the hot spring ions showed pre-seismic anomalous variations at different time periods in the seismogenic region. The characteristics of Earth’s multi-sphere coupling anomalies in temporal evolution and spatial distribution were obvious, which validated the Lithosphere–Atmosphere–Ionosphere Coupling (LAIC) mechanism. Finally, combining the analysis results and the LAIC mechanism, we suggested that the multi-sphere coupling anomalies were more likely associated with the Luding Ms6.8 EQ, and that the differential motion and the regional crustal stress accumulation between the Chuandian block and the Bayan Har block might have led to this EQ. Furthermore, remote sensing and ground-based monitoring technologies can play an important role in corroborating and compensating each other, while further study of the multi-sphere coupling mechanism will provide a clearer understanding of the seismogenic process for major EQs.