In-band interferers in wireless communication channels are due to the high order harmonics of multiple clock frequencies used by baseband digital signal processing in a single-chip solution. The impacts of in-band spurious tones on wireless performance are explored with hardware-in-the-loop simulation (HILS) of the LTE compliant systems. RF receiver circuits fabricated in a 65 nm CMOS technology are involved in the HILS, for combining circuit-level interactions at the front end and system-level digital signal processing in the back end. Experiments exhibit the sensitivity of LTE communication throughput against substrate coupling noise from a digital noise emulator to the RF receiver circuits on the same chip. The observed response is equivalently confirmed with the input referred RF sinusoidal noise components intentionally added to the input RF signal with LTE modulation. The HILS enables hierarchical diagnosis of a wireless communication system from circuit-level interactions to system-level responses against noise coupling.