COWPEA mosaic virus (CPMV) has been identified as an economically critical pathogen infecting cowpea plants. Recently, eco-friendly strategies to enhance the tolerance level of crops against virus infection have been developed. The present investigation evaluates the effect of salicylic acid (SA) on the response of three cultivars of Vigna unguiculata plants [Libyan black eye (LB), Libyan red eye (LR), and Egyptian black eye hybrid (Kafr El Sheikh1cultivar; (EBH)] to CPMV. The leaves of 15-day old cowpea plants were foliar sprayed with 50 or 100 μM SA, 24 h before inoculation with CPMV. Most measured growth indices, total photosynthetic pigment, and photosynthetic efficiency were diminished in CPMV-inoculated plants of all three cultivars. SA utilization could enhance cowpea growth and lower virus severity, most notably in the Libyan cultivars. Furthermore, the CPMV-induced oxidative damages and phenolics accumulation were noted to decrease upon SA application to all infected cowpea cultivars. CPMV infection triggered an increase in catalase (CAT), guaiacol peroxidase (GPX), and polyphenol oxidase (PPO) activity in all cultivars, except for EBH where PPO was insignificantly changed. Interestingly, SA pretreatment was observed to significantly inhibit CAT activity in the Libyan cultivars compared to infected plants. It also induced GPX and PPO in all three tested cultivars, most obviously in the Libyan ones. In general, SA was effective in inducing of systematic resistance to CPMV in the two Libyan cowpea cultivars but not in the Egyptian one.