The Cape Town club, who have links to former European champions Ajax Amsterdam, lost at home on Wednesday and have taken just two points from six league matches to lie second last.
They were also knocked out of the League Cup last weekend in a match temporarily halted when a sudden gust of wind blew advertising boards on to the pitch.
Mozambique-born De Sa, 52, won one cap for South Africa as a goalkeeper and experienced several coaching highlights before his downturn this season.
He guided famed Soweto club Orlando Pirates to the 2013 CAF Champions League final, where they lost 3-1 overall to Egyptian giants Al Ahly.
De Sa quit Pirates for Ajax two years ago and led the Cape Town outfit to the Top 8 Cup last season, beating favourites Kaizer Chiefs in the final.
French coach Denis Lavagne was fired by Free State Stars after the first three league matches failed to yield a win and Italian Giovanni Solinas took his place.
Promoted Highlands Park dumped Allan Freese following one victory in five Premiership matches and hired former South Africa coach Gordon Igesund.