Multi-electrode arrays (MEAs) are being more widely used by researchers as an instrument platform for monitoring prolonged, non-destructive recordings of spontaneously firing neurons for applications in modeling Alzheimer's, Parkinson's, schizophrenia, and many other diseases of the human CNS. With the more widespread use of these instruments, there is a need to examine the prior art of studies utilizing MEAs and delineate best practices for data acquisition and analysis to avoid errors in interpretation of the resultant data. Using a dataset of recordings from primary rat () cortical cultures, methods and statistical power for discerning changes in neuronal activity on the array level are examined. Further, a method for unsupervised spike sorting is implemented, allowing for the resolution of action potential incidents down to the single neuron level. Following implementation of spike sorting, the dynamics of firing frequency across populations of individual neurons and networks are examined longitudinally. Finally, the ability to detect a frequency independent phenotype, the change in action potential amplitude, is demonstrated through the use of pore-forming neurotoxin treatments. Taken together, this study provides guidance and tools for users wishing to incorporate multi-well MEA usage into their studies.