Mutations of the voltage gated Na+ channel NaV1.1 (SCN1A) are important causes of different genetic epilepsies and can also cause familial hemiplegic migraine (FHM-III). In previous studies, some rescuable epileptogenic folding defective mutants located in domain IV of NaV1.1 have been identified, showing partial loss of function also with maximal rescue. Variable rescue may be one of the causes of phenotypic variability, and rescue might be exploited for therapeutic approaches. Recently, we have identified a folding defective FHM-III NaV1.1 mutant that showed overall gain of function when rescued, consistent with a differential pathomechanism. Here, we have evaluated functional properties and cell surface expression of six NaV1.1 epileptogenic missense mutations in different rescuing conditions, including a novel one that we have developed expressing a selective sodium channel toxin (CsEI) targeted to the endoplasmic reticulum (ER). All the mutants showed loss of function and reduced cell surface expression, consistently with possibility of rescue. Four of them were rescuable by incubation at low temperature and interactions with different co-expressed proteins or a pharmacological chaperone (phenytoin). Notably, CsEI was able to rescue four mutants. Thus, NaV1.1 folding defective mutants can be relatively common and mutations inducing rescuable folding defects are spread in all NaV1.1 domains. Importantly, epileptogenic mutants showed overall loss of function even upon rescue, differently than FHM-III ones. The effectiveness of CsEI demonstrates that interactions in the ER are sufficient for inducing rescue, and provides a proof of concept for developing possible therapeutic approaches that may overcome some limitations of pharmacological chaperones. •We studied functional effects of six NaV1.1 epileptogenic missense mutations.•They showed loss of function and reduced surface expression, possibly because of rescuable folding defects.•Four of them were rescuable by low temperature or interactions with proteins or drugs.•We developed a new rescue method which may overcome some limitations of existing ones.•All mutants showed loss of function even upon rescue, differently than migraine ones.