Despite the marked influence of relative humidity (RH) on ecosystems and human society, the spatiotemporal pattern of RH is far from clearly understood. This study analyzed the spatiotemporal variation in RH in Guangdong Province, South China, in the period of 1959–2017. The RH data were collected from 74 national standard meteorological stations. The spatiotemporal variation in RH was evaluated using rotate empirical orthogonal function (REOF) zoning, Mann–Kendall test, and wavelet transform methods. Based on the REOF decomposition situation of monthly RH field, Guangdong was divided into six subareas. The annual mean of RH in the whole province was 78.90%. In terms of spatial variation, overall annual mean RH decreased from southwest to northeast in the province. Temporally, annual mean RH showed a declining trend in the last six decades. Particularly, the RH in the Pearl River Delta area declined at the rate of 1.349%/10a. Mann–Kendall tests showed that mutation points of annual mean RH mostly appeared in the 1990s, especially in the early 1990s. Continuous wavelet transforms of annual mean RH displayed that inland subareas have similar cycle characteristics, and the east coast and Pearl River Delta have no significant period in most time domains. The results provide new understanding of RH variation in the last six decades in South China, which is valuable for detecting climate change, monitoring hazardous weather, and predicting future environmental change.