The Siding Pb-Zn deposit is located in the transition zone between the Yangtze Craton and the Cathaysian Block on the southwestern margin of the Jiangnan Orogenic Belt and is a representative example of the Pb-Zn deposits found in northern Guangxi, South China. In this study, sphalerite Rb-Sr dating and C-O-S-Pb isotope analyses were used to investigate the mineralization age and source of the ore-forming minerals in the Siding Pb-Zn deposit. The d13CPDB and d18OSMOW values of the gangue mineral calcites were determined to be between -5.0 and -1.1 (average = -2.6) and between 13.2 and 18.4 (average = 16.4), respectively. These values are roughly consistent with those of the carbonate minerals in the ore-hosting strata, namely, -1.63 to 0.83 (average = -0.34) and 19.0-22.0 (average = 20.9), respectively, indicating a mainly sedimentary origin of the ore-forming fluids. The delta S-34 values of the ore minerals were determined to be -17.1 to 5.1 (average = -2.6), while they were -8.6 to 5.1 (average = -0.8) for sphalerite, -7.8 to 2.7 (average = -1.6) for galena, and -17.1 to 2.3 (average = -7.3) for pyrite. The Pb-206/Pb-204, Pb-207/Pb-204, and Pb-208/Pb-204 ratios of the sulfides (pyrite, galena, and sphalerite) were determined to be 18.12-18.76 (average = 18.50), 15.66-15.97 (average = 15.80), and 38.36-39.71 (average = 38.96), respectively, which are consistent with those of limestone in the region (Pb-206/Pb-204 = 17.65-18.77, Pb-207/Pb-204 = 15.60-15.91, and Pb-208/Pb-204 = 37.82-39.59). Pb and S isotope analyses showed that the ore-forming materials originated from the crust, as also substantiated by the (Sr-87/Sr-86)(i) ratios (0.710806-0.713740) of the sphalerite. The isochron age determined by Rb-Sr dating was 360 +/- 5.0 Ma, indicating the formation of the Siding deposit in the Late Devonian (Hercynian Period). This mineralization age substantially differs from those determined for the Dachang, Tongshanling, Huangshaping, and Shuikoushan Pb-Zn deposits on the southern margins of the Jiangnan Orogenic Belt, but is comparable with those of the adjacent Daliangzi, Bokouchang, and Dadongla Pb-Zn deposits in northeastern Guizhou. We therefore propose that the formation of the Siding Pb-Zn deposit is related to a basin-scale fluid flow induced by Late Devonian extensional rifting in South China, in response to the tectonic evolution of the southwestern Yangtze Craton.