Intracortical electrodes record neural signals directly from local populations of neurons in the brain, and conduct them to external electronics that control prosthetics. However, the relationship between electrode design, defined by shape, size and tethering; and long-term (chronic) stability of the neuron-electrode interface is poorly understood. Here, we studied the effects of various commercially available intracortical electrode designs that vary in shape (cylindrical, planar), size (15 μm, 50 μm and 75 μm), and tethering [electrode connections to connector with (tethered) and without tethering cable (untethered)] using histological, transcriptomic, and electrophysiological analyses over acute (3 day) and chronic (12 week) timepoints. Quantitative analysis of histological sections indicated that Michigan 50 μm (M50) and Michigan tethered (MT) electrodes induced significantly (p < 0.01) higher glial scarring, and lesser survival of neurons in regions of blood-brain barrier (BBB) breach when compared to microwire (MW) and Michigan 15 μm (M15) electrodes acutely and chronically. Gene expression analysis of the neurotoxic cytokines interleukin (Il)1 (Il1α, Il1β), Il6, Il17 (Il17a, Il17b, Il17f), and tumor necrosis factor alpha (Tnf) indicated that MW electrodes induced significantly (p < 0.05) reduced expression of these transcripts when compared to M15, M50 and FMAA electrodes chronically. Finally, electrophysiological assessment of electrode function indicated that MW electrodes performed significantly (p < 0.05) better than all other electrodes over a period of 12 weeks. These studies reveal that intracortical electrodes with smaller size, cylindrical shape, and without tethering cables produce significantly diminished inflammatory responses when compared to large, planar and tethered electrodes. These studies provide a platform for the rational design and assessment of chronically functional intracortical electrode implants in the future.