Kv7 channels are a set of five evolutionarily closely related voltage-gated potassium channels (Kv7.1-Kv7.5) that underpin diverse physiological functions, such as cardiac rhythm (Kv7.1/KCNE1), hearing (Kv7.4) and neuronal excitability (Kv7.2-5). Finding strategies to selectively target these channels provides novel opportunities for drug development. The antiseizure drug cannabidiol (CBD) has been shown to inhibit Kv7.1/KCNE1 but activate Kv7.2/Kv7.3. To investigate how CBD and potentially other phytocannabinoids elicit these effects on the channel and ligand level, electrophysiological and computational methods were employed. For the pharmacological description of phytocannabinoids, the automated planar patch clamp (APC) technique with Kv7-CHO-cell lines, and the two-electrode voltage clamp technique with Xenopus laevis oocytes transiently expressing Kv7 channels, were used. Coarse-grained simulations or Chai-1, an AI-method, predicted possible binding sites; experimental mutagenesis of Kv7 channels in oocytes was used to test these predictions. To determine which moieties were critical for phytocannabinoid effects, APC data was related to phytocannabinoid chemical structures alongside testing of semi-synthetic cannabinoids in oocytes. Our findings showed that CBD’s action on Kv7 channels can be broadly divided into three categories: augmentation (Kv7.4, Kv7.5, Kv7.4/Kv7.5, Kv7.3/Kv7.5), potentiation (Kv7.2, Kv7.3, Kv7.2/Kv7.3) and inhibition (Kv7.1, Kv7.1/KCNE1). Actions of other phytocannabinoids could also be subdivided along these categories, with exceptions. For the inhibited channels, we posited separate CBD binding sites in Kv7.1 and Kv7.1/KCNE1. For the potentiated Kv7.2 and augmented Kv7.4 channels, we proposed a similar binding site which overlapped with that of another antiseizure drug. This site was later confirmed independently for Kv7.2 along with an adjacent site. Our data suggests that this adjacent site might also exist in Kv7.4. On the ligand level, chirality and alkyl-chain length informed how CBD acted on Kv7.2/Kv7.3 and Kv7.4 channels but not Kv7.1/KCNE1. Modifications to the CBD structure as semi-synthetic cannabinoids revealed that CBD is likely already optimal for Kv7.4 activation. In conclusion, this work provides novel insights into how the antiseizure drug CBD and other phytocannabinoids modulate Kv7 channels, and how these insights might be used for the development of Kv7 subtype-selective drugs. It also provides new insights into the putative mechanisms of action underlying both the therapeutic effects and side effects of clinically used phytocannabinoids.