As a national regional development strategy and a vital region of the Belt and Road Initiative, the sustainable development of the Pan-Pearl River Delta (Pan-PRD) region is of great importance. The national development plan emphasizes improving total factor productivity (TFP) and promoting high-quality economic development. This paper uses the DEA-Malmquist index model to measure the TFP of nine provinces in the Pan-PRD region based on inter-provincial panel data from 2003 to 2020. Furthermore, it analyzes its growth trend and heterogeneity characteristics in the inter-provincial spatial, industrial, and city dimensions. The results show that in the time dimension, TFP shows a W-shaped fluctuation trend, technical efficiency grows slowly, and technical progress is the pillar of TFP improvement. The spatial dimension shows a high distribution in the center and low distribution in the south. On the industry dimension, the TFP is in descending order as follows: tertiary industry—secondary industry—primary industry. The spatial distribution is heterogeneous, exacerbating the uneven economic development within the region, and the regional industrial structure needs urgent optimization. The spatial development of city TFP is uneven, and the number of cities with a TFP below 1 is increasing. Finally, we suggest policies to accelerate regional collaborative innovation, cultivate advantageous industrial clusters, create an advantageous industrial ecosystem, and achieve sustainable development in the Pan-PRD region.