Football's world governing body has confirmed its independent review committee has cleared Samoura to replace Jerome Valcke.
Samoura spent 21 years working for the United Nations and becomes Fifa's first female secretary general.
The 54-year-old will work alongside new president Gianni Infantino.
Fifa is desperate to repair its image following a series of corruption allegations under previous president Sepp Blatter and Valcke.
Blatter has been suspended from all football-related activities for six years and Valcke has been banned from all football-related activities for 12 years.
Senegalese Fatma Samoura will begin work in her new role as Fifa secretary general on Monday after successfully passing an eligibility check.