Reactive multilayers comprising alternating nanoscale layers of Al and Ni, exhibit potential across various applications, including localized heating for welding and joining. Control over reaction properties is pivotal for emerging applications, such as chemical time delays or neutralization of biological or chemical weapons. This research offers insights into the intricate interplay between substrate thickness, surface roughness, and the behavior of Al/Ni reactive multilayers, opening avenues for tailored applications in various domains. To observe this interplay, silica with various thicknesses from 0.4 µm to 1.6 µm was deposited on polished single crystalline Si and rough poly‐Si base substrates. Additionally, to analyze the impact of varying silica thickness along the sample length on reaction behavior, silica in step‐like shape was fabricated. Subsequently, Al/Ni multilayers with 5 µm total thickness and 20 or 50 nm bilayer periodicities were deposited. Reaction velocity and temperature were monitored with a high‐speed camera and pyrometer. Results indicate that silica thickness significantly affects self‐propagation in multilayers. The reaction is not self‐sustained for silica layers ≤ 0.4 µm, depending on bilayer periodicity and substrate roughness. The velocity increases or decreases based on the direction of reaction propagation, whether it moves upwards or downwards, in relation to the thickness of silica.This article is protected by copyright. All rights reserved.