Significance Although the genetic basis of HD is known, the molecular mechanisms underlying neuronal dysfunction remain unclear. Combining electrophysiological and transcriptional analyses of single neurons (Patch-sequencing [Patch-seq]), this study connects transcriptional dysregulation and synaptic transmission deficits, two key disease features, in HD. We identify a number of genes whose expression changes are correlated with physiological deficiencies in mutant Htt neurons. We validate the use of the Patch-seq system for screening and identifying potential therapeutic interventions. We show that pharmacological inhibition of an epigenetic regulator rectifies several functional, morphological, and transcriptional deficits in mutant neurons. This work suggests previously unknown gene–neuronal function relationships as potential targets in HD and also highlights advances in single-cell transcriptomics and their use in understanding human disease.