Low soil fertility is a major constraint for maize production in West Africa, the use of legumes as living mulch improves soil fertility and yield of main crops. However, there is limited literature on the appropriate time to plant living mulch in maize-based cropping system in West Africa. A 2-year (2017-2018) study was conducted to determine the effect of cowpea living mulch (CPLM) on soil quality and grain yield in maize-based cropping system of northern Ghana. A factorial treatment combination of three maize maturity types (extra-early, early and medium) and four CPLM methods (control, CPLM with maize planted on the same day, CPLM planted 1 week after maize and CPLM planted 2 weeks after maize) was laid out in a randomized complete block design with four replications in Northern and Upper East regions of Ghana. Principal component and correlation matrix analyses were used to select minimum data set for soil quality index (SQI) calculation. The SQI for CPLM improved by 50-100% relative to that of the control in both seasons and regions. The CPLM significantly increased maize grain by 34-37% during both seasons in Northern Region and 84% during 2017 in the Upper East Region compared with that of the control. The effect of time of planting CPLM on grain yield showed negative correlation with amount of rainfall received during vegetative growth of CPLM. The results suggest that smallholder maize-based farmers in northern Ghana and similar agro-ecologies in West Africa can plant CPLM 1-2 weeks after planting maize to improve soil quality and increase maize grain yield.