We present a novel 21-core homogeneous multi-core fiber (MCF) structure with three different types of core placement layouts (1-Ring, 2-Ring, and Square Lattice) and densely pack the cores with a minimum cladding diameter of 200  μm to support high-speed applications. In the first phase, three MCF structures (1-Ring, 2-Ring, and Square Lattice) were designed with a step refractive index (RI) profile under the limited cladding thickness and diameter of 35 and 200  μm, respectively, and their crosstalk was calculated. In the second phase, all three structures were designed with a low-RI trench-assisted (TA) profile to significantly reduce the crosstalk. To further suppress the crosstalk, air holes were placed between the TA cores, and it was found that the TA Square Lattice core arrangement with air holes achieved the minimum crosstalk value of approximately −70  dB  /  100  km. The impact of important design parameters, such as transmission distance, bending radius, operating wavelength, and core diameter on inter-core crosstalk for all three design structures for both RI profiles and air-hole arrangement were numerically analyzed. Furthermore, other transmission characteristics, such as group delay and dispersion concerning wavelength, were analyzed for the above-stated design structures.